Guanidinyl heterocycle compounds useful as alpha-2 adrenoceptor agonists

ABSTRACT

This invention involves compounds having the following structure:                    
     as described in the claims; and enantiomers, optical isomers, stereoisomers, diastereomers, tautomers, addition salts, biohydrolyzable amides and esters thereof, as well as pharmaceutical compositions comprising such novel compounds. The invention also relates to the use of such compounds for preventing or treating disorders modulated by alpha-2 adrenoceptors.

CROSS REFERENCE

This application is a 371 of PCT/US97/20802, filed Nov. 21, 1997 andclaims priority under Title 35, United States Code 119(e) fromProvisional Application Ser. No. 60/032,023, filed Nov. 25, 1996.

TECHNICAL FIELD

This invention relates to certain substituted guanidinyl heterocyclecompounds. The compounds have been found to be alpha-2 adrenoceptoragonists and are useful for treatment of disorders modulated by alpha-2adrenoceptors.

BACKGROUND OF THE INVENTION

Therapeutic indications of alpha-2 adrenoceptor agonists have beendiscussed in the literature: Ruffolo, R. R., A. J. Nichols, J. M.Stadel, & J. P. Hieble, “Pharmacologic and Therapeutic Applications ofAlpha-2 Adrenoceptor Subtypes”, Annual Review of Pharmacology &Toxicology, Vol. 32 (1993) pp. 243-279.

Information regarding alpha adrenergic receptors, agonists andantagonists, in general, and regarding compounds related in structure tothose of this invention are disclosed in the following references:Timmermans, P. B. M. W. M., A. T. Chiu & M. J. M. C. Thoolen, “12.1α-Adrenergic Receptors”, Comprehensive Medicinal Chemistry, Vol. 3,Membranes & Receptors, P. G. Sammes & J. B. Taylor, eds., Pergamon Press(1990), pp. 133-185; Timmermans, P. B. M. W. M. & P. A. van Zwieten,“α-Adrenoceptor Agonists and Antagonists”, Drugs of the Future, Vol. 9,No. 1, (January, 1984), pp. 41-55; Megens, A. A. H. P., J. E. Leysen, F.H. L. Awouters & C. J. E. Niemegeers, “Further Validation of in vivo andin vitro Pharmacological Procedures for Assessing the α₁ andα₂-Selectivity of Test Compounds: (2) α-Adrenoceptor Agonists”, EuropeanJournal of Pharmacology, Vol. 129 (1986), pp. 57-64; Timmermans, P. B.M. W. M., A. de Jonge, M. J. M. C. Thoolen, B. Wilffert, H. Batink & P.A. van Zwieten, “Quantitative Relationships between α-AdrenergicActivity and Binding Affinity of α-Adrenoceptor Agonists andAntagonists”, Journal of Medicinal Chemistry, Vol. 27 (1984) pp.495-503; van Meel, J. C. A., A. de Jonge, P. B. M. W. M. Timmernans & P.A. van Zwieten, “Selectivity of Some Alpha Adrenoceptor Agonists forPeripheral Alpha-1 and Alpha-2 Adrenoceptors in the Normotensive Rat”,The Journal of Pharmacology and Experimental Therapeutics, Vol. 219, No.3 (1981), pp. 760-767; Chapleo, C. B., J. C. Doxey, P. L. Myers, M.Myers, C. F. C. Smith & M. R. Stillings, “Effect of 1,4-DioxanylSubstitution on the Adrenergic Activity of Some Standardα-Adrenoreceptor Agents”, European Journal of Medicinal Chemistry, Vol.24 (1989), pp. 619-622; Chapleo, C. B., R. C. M. Butler, D. C. England,P. L. Myers, A. G. Roach, C. F. C. Smith, M. R. Stillings & I. F.Tulloch, “Heteroaromatic Analogues of the α₂-Adrenoreceptor PartialAgonist Clonidine”, Journal of Medicinal Chemistry, Vol. 32 (1989), pp.1627-1630; Clare, K. A., M. C. Scrutton & N. T. Thompson, “Effects ofα₂-Adrenoceptor Agonists and of Related Compounds on Aggregation of, andon Adenylate Cyclase Activity in, Human Platelets”, British Journal ofPharmacology, Vol. 82 (1984), pp. 467-476; U.S. Pat. No. 3,890,319issued to Danielewicz, Snarey & Thomas on Jun. 17, 1975; and U.S. Pat.No. 5,091,528 issued to Gluchowski on Feb. 25, 1992. However, manycompounds related in structure to those of this invention do not providethe activity and specificity desirable when treating disorders modulatedby alpha-2 adrenoceptors.

For example, many compounds found to be effective nasal decongestantsare frequently found to have undesirable side effects, such as causinghypertension and insomnia at systemically effective doses. There is aneed for new drugs which provide relief from nasal congestion withoutcausing these undesirable side effects.

OBJECTS OF THE INVENTION

It is an object of the invention to provide compounds and compositionsuseful in treating disorders modulated by alpha-2 adrenoceptors.

It is an object of this invention to provide novel compounds havingsubstantial activity in preventing or treating nasal congestion, otitismedia, and sinusitis, without undesired side effects.

It is also an object of this invention to provide novel compounds fortreating cough, chronic obstructive pulmonary disease (COPD) and/orasthma.

It is also an object of this invention to provide novel compounds fortreating diseases and disorders associated with sympathetic nervoussystem activity, including benign prostatic hypertrophy, cardiovasculardisorders comprising myocardial ischemia, cardiac reperfusion injury,angina, cardiac arrhythmia, heart failure and hypertension.

It is also an object of this invention to provide novel compounds fortreating ocular disorders, such as ocular hypertension, glaucoma,hyperemia, conjunctivitis and uveitis.

It is also an object of this invention to provide novel compounds fortreating gastrointestinal disorders, such as diarrhea, irritable bowelsyndrome, hyperchlorhydria (hyperacidity) and peptic ulcer (ulcer).

It is also an object of this invention to provide novel compounds fortreating migraine.

It is also an object of this invention to provide novel compounds fortreating pain, substance abuse and/or withdrawal.

It is a still further object of this invention to provide such compoundswhich have good activity from peroral, parenteral, intranasal and/ortopical dosing.

SUMMARY OF THE INVENTION

This invention relates to compounds having the following structure:

a) R₁ is hydrogen; or alkyl or nil; where R₁ is nil, bond (a) is adouble bond;

b) D is CR₂ and R₂ is selected from hydrogen; unsubstituted C₁-C₃alkanyl; amino, hydroxy, mercapto; C₁-C₃ alkylthio or alkoxy; C₁-C₃alkylamino or C₁-C₃ dialkylamino and halo; or when B is CR₃; D may be N;

c) B is NR₉, CR₃═CR₈, CR₃═N, CR₃, S, O, SO or SO₂; wherein R₉ isselected from hydrogen; unsubstituted C₁-C₃ alkanyl, alkenyl or alkynyl;cycloalkanyl, cydoalkenyl; and wherein R₃ and R₈ are each independentlyselected from hydrogen; unsubstituted C₁-C₃ alkanyl, alkenyl or alkynyl;cycloalkanyl, cycloalkenyl; unsubstituted C₁-C₃ alkylthio or alkoxy;hydroxy; thio; nitro; cyano; amino; C₁-C₃ alkylamino or C₁-C₃dialkylamino and halo;

d) R₄, R₅ and R₆ are each independently selected from hydrogen;unsubstituted C₁-C₃ alkanyl, alkenyl or alkynyl; cycloalkanyl,cycloalkenyl; unsubstituted C₁-C₃ alkylthio or alkoxy; hydroxy; thio;nitro; cyano; amino; C₁″C₃ alkylamino or C₁-C₃ dialkylamino; halo; andNH—C(═NR₁₀)NHR₁₁ (guanidinyl); wherein R₁₀ and R₁₁ are independentlyselected from hydrogen; methyl; and ethyl; and wherein one and only oneof R₄, R₅ and R₆ is guanidinyl;

e) R₇ is selected from hydrogen; unsubstituted C₁-C₃ alkanyl, alkenyl oralkynyl; cycloalkanyl, cycloalkenyl; unsubstituted C₁-C₃ alkylthio oralkoxy; hydroxy; thio; nitro; cyano; amino; C₁-C₃ alkylamino or C₁-C₃dialkylamino and halo;

and enantiomers, optical isomers, stereoisomers, diastereomers,tautomers, addition salts, biohydrolyzable amides and esters, andpharmaceutical compositions containing such novel compounds, and the useof such compounds for preventing or treating disorders modulated byalpha-2 adrenoceptors.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, “alkanyl” means a saturated hydrocarbon substituent,straight or branched chain, unsubstituted or substituted.

As used herein, “alkenyl” means a hydrocarbon substituent with onedouble bond, straight or branched chain, unsubstituted or substituted.

As used herein, “alkylthio” means a substituent having the structureQ—S—, where Q is alkanyl or alkenyl.

As used herein, “alkoxy” means a substituent having the structure Q—O—,where Q is alkanyl or alkenyl.

As used herein, “alkylamino” means a substituent having the structureQ—NH—, where Q is alkanyl or alkenyl.

As used herein, “dialkylamino” means a substituent having the structureQ₁—N(Q₂)—, where each Q is independently alkanyl or alkenyl.

“Guanidinyl” is defined as a radical of structure;

For purposes of exemplifying this radical, wherever it appears in achart, it is shown as “GNDNL” for brevity.

“Halo”, “halogen”, or “halide” is a chloro, bromo, fluoro or iodo.

A “pharmaceutically-acceptable salt” is a cationic salt formed at anyacidic (e.g., carboxyl) group, or an anionic salt formed at any basic(e.g., amino) group. Many such salts are known in the art, as describedin World Patent Publication 87/05297, Johnston et al., published Sep.11, 1987, incorporated by reference herein. Preferred cationic saltsinclude the alkali metal salts (such as sodium and potassium), alkalineearth metal salts (such as magnesium and calcium) and organic salts.Preferred anionic salts include halides, sulfonates, carboxylates,phosphates, and the like. Clearly contemplated in such salts areaddition salts that may provide an optical center, where once there wasnone. For example, a chiral tartrate salt may be prepared from thecompounds of the invention, and this definition includes such chiralsalts.

The compounds of the invention are sufficiently basic to formacid-addition salts. The compounds are useful both in the free base formand the form of acid-addition salts, and both forms are within thepurview of the invention. The acid-addition salts are in some cases amore convenient form for use. In practice, the use of the salt forminherently amounts to the use of the base form of the active. Acids usedto prepare acid-addition salts include preferably those which produce,when combined with the free base, medicinally acceptable salts. Thesesalts have anions that are relatively innocuous to the animal organism,such as a mammal, in medicinal doses of the salts so that the beneficialproperty inherent in the free base are not vitiated by any side effectsascribable to the acid's anions.

Examples of appropriate acid-addition salts include, but at not limitedto hydrochloride, hydrobromide, hydroiodiode, sulfate, hydrogensulfate,acetate, trifluoroacetate, nitrate, maleate, citrate, fumarate, formate,stearate, succinate, mallate, malonate, adipate, glutarate, lactate,propionate, butyrate, tartrate, methanesulfonate,trifluoromethanesulfonate, p-toluenesulfonate, dodecyl sulfate,cyclohexanesulfamate, and the like. However, other appropriatemedicinally acceptable salts within the scope of the invention are thosederived from other mineral acids and organic acids. The acid-additionsalts of the basic compounds are prepared by several methods. Forexample the free base can be dissolved in an aqueous alcohol solutioncontaining the appropriate acid and the salt is isolated by evaporationof the solution. Alternatively, they may be prepared by reacting thefree base with an acid in an organic solvent so that the salt separatesdirectly. Where separation of the salt is difficult, it can beprecipitated with a second organic solvent, or can be obtained byconcentration of the solution.

Although medicinally acceptable salts of the basic compounds arepreferred, all acid-addition salts are within the scope of the presentinvention. All acid-addition salts are useful as sources of the freebase form, even if the particular salt per se is desired only as anintermediate product. For example, when the salt is formed only forpurposes of purification or identification, or when it is used as anintermediate in preparing a medicinally acceptable salt by ion exchangeprocedures, these salts are clearly contemplated to be a part of thisinvention.

“Biohydrolyzable amide” refers to an amide of the compound of theinvention that is readily converted in vivo by a mammal subject to yieldan active compound of the invention.

A “biohydrolyzable ester” refers to an ester of the compound of theinvention that is readily converted by a mammal subject to yield anactive compound of the invention.

“Optical isomer”, “stereoisomer”, “enantiomer,” “diastereomer,” asreferred to herein have the standard art recognized meanings (Cf.,Hawleys Condensed Chemical Dictionary, 11th Ed.). Of course, an additionsalt may provide an optical center, where once there was none. Forexample, a chiral tartrate salt may be prepared from the compounds ofthe invention, and this definition includes such chiral salts. It willbe apparent to the skilled artisan that disclosure of the racemicmixture alone discloses any enantiomers therein. Thus by one disclosure,more than one compound is taught.

As used herein “animal” includes “mammals” which includes “humans”.

The skilled artisan will appreciate that tautomeric forms will exist incertain compounds of the invention. For example, when R₂ is hydroxy andbond (a) is a double bond, it is understood to include the keto form ofthat molecule, where R₂ is oxo, and bond (a) is a single bond, thoughnot specifically described. Thus, in this description the disclosure ofone tautomeric form discloses each and all of the tautomers. Similarly,when tautomer A of the molecule is shown, it is understood to includetautomers B and C of that molecule although not specifically depicted.

The illustration of specific protected forms and other derivatives ofthe Formula (I) compounds is not intended to be limiting. Theapplication of other useful protecting groups, salt forms, etc. iswithin the ability of the skilled artisan.

As defined above and as used herein, substituent groups may themselvesbe substituted. Such substitution may be with one or more substituents.Such substituents include those listed in C. Hansch and A. Leo,Substituent Constants for Correlation Analysis in Chemistry and Biology(1979), incorporated by reference herein. Preferred substituents include(for example) alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, amino,aminoalkyl (e.g., aminomethyl, etc.), cyano, halo, carboxy, alkoxyacetyl(e.g., carboethoxy, etc.), thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl (e.g., piperidinyl, morpholinyl, pyrrolidinyl, etc.),imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl, and combinationsthereof.

For the purposes of nomenclature, as shown in the following example, thelocation of the guanidinyl radical is:

It is recognized that where B is CR₃═CR₈ and the like, this numbering isnot in strict compliance with IUPAC nomenclature. It is used forillustration of synthetic methods only; examples of compounds have nameswhich more closely resemble IUPAC nomenclature.

Compounds

This invention includes compounds having the following structure:

as described in the Summary of the Invention.

In the above structure, when the guanidinyl is at the 6-position,preferably R₇ is selected from hydrogen; unsubstituted alkanyl oralkenyl having from 1 to about 3 carbon atoms; unsubstituted alkylthioor alkoxy having from 1 to about 3 carbon atoms; hydroxy; thiol; cyano;and halo. R₄ is preferably hydrogen, cyano, halo or methyl. R₇ is alsopreferably alkanyl, more preferably methyl or ethyl, most preferablymethyl. R₇ which is alkylthio or alkoxy is preferably saturated, alsopreferably C₁ or C₂, most preferably methylthio or methoxy. R₇ which ishalo is preferably chloro or bromo.

In the above structure, when the guanidinyl is at the 5-position,preferably R₄ is selected from hydrogen; unsubstituted alkanyl oralkenyl having 1 to about 3 carbon atoms; unsubstituted alkylthio oralkoxy having from 1 to about 3 carbon atoms; hydroxy; thiol; cyano; andhalo. R₇ is preferably alkanyl or halo. R₄ and R₇ are most preferablymethyl.

In the above structure, when the guanidinyl is at the 4-position,preferably R₇ is selected from hydrogen; unsubstituted alkanyl oralkenyl having from 1 to about 3 carbon atoms; hydroxy; thiol; cyano;and halo. R₇ which is alkanyl, is preferably methyl or ethyl, morepreferably methyl. R₇ which is halo is preferably chloro or bromo. R₆ ispreferably hydrogen; alkanyl; cyano; and halo. R₆ which is alkanyl ispreferably methyl or ethyl, most preferably methyl. R₅ is preferablyhydrogen; alkanyl; and halo. R₅ which is alkanyl is preferably methyl orethyl, most preferably methyl.

Preferred compounds of this invention have the following structure:

where R₁ is nil, (a) is a double bond and D, B, R₄, R₅, R₇ and R₁₀ areas indicated in the following table:

Compound No D B R₄ R₅ R₇ R₁₀ 1 CH NH H H Me H 2 CH NH Me H Me H 3 CH—MeNH H H Me H 4 CH N—Me H H Me H 5 CH NH H H Br H 6 CH NH H H Me Me 7 CHCH═CH H H Me H 8 CH CH═CH H H Br H 9 CH S H Me H H 10  CH S H H Br H

Methods of making the compounds of the invention

The compounds of this invention are synthesized using the followingprocedures. For purposes of this description, 6-guanidinyl compounds areshown, but the skilled artisan will appreciate that the 4- and5-guanidinyl compounds are prepared similarly. The R₁-R₇ radicals areomitted for clarity, unless they are prepared in that specific scheme.The skilled artisan will appreciate that the radicals omitted are addedusing techniques known in the art. The skilled artisan will alsoappreciate that the methods described may be used with blocking groupsand the like, as appropriate.

Guanidinyl groups are conveniently prepared from nitro and aminocompounds via the following example synthetic sequences:

Preferably these compounds are made from nitro or amino compounds.(Nitro and amino compounds are made by known processes.) The compoundsmay be manipulated to result in the suitably substitutedaminoheterocycle. This aminoheterocycle is then subjected to knownmethods to produce the guanidinyl derivative. For example, the aminocompound may be reacted with cyanamide (H₂NCN) in acid to provide theguanidinyl compound. Alternatively, the amino compound may be reactedwith a guanidine precursor, such as an alkyl pseudothiourea or protectedalkyl pseudothiourea in the presence of a mercuric salt or the like.

The above starting nitro and amino compounds are obtained via one ormore synthetic steps comprising alkylations, halogenations (usuallybrominations), and halogen displacement reactions. These reaction typesare summarized below;

Preferably, chlorination is accomplished using Cl₂, and iodination, byICI using the same reactions.

It will be apparent to the skilled artisan that the reactionsillustrated above are known reactions. Furthermore, it is within thepurview of the skilled artisan to vary these reactions to preparecompounds within the scope of the claims.

In the above schemes, where an R is alkoxy or alkylthio, thecorresponding hydroxy or thiol compounds are derived from the finalcompounds by using a standard dealkylating procedure (Bhatt, et al.,“Cleavage of Ethers”, Synthesis, 1983, pp. 249-281).

The starting materials used in preparing the compounds of the inventionare known, made by known methods, or are commercially available as astarting material.

It is recognized that the skilled artisan in the art of organicchemistry can readily carry out manipulations without further direction,that is, it is well within the scope and practice of the skilled artisanto carry out these manipulations. These include reduction of carbonylcompounds to their corresponding alcohols, oxidations, acylations,aromatic substitutions, both electrophilic and nucleophilic,etherifications, esterifications and saponifications and the like. Thesemanipulations are discussed in standard texts such as March, AdvancedOrganic Chemistry (Wiley), Carey and Sundberg, Advanced OrganicChemistry (2 vol.) and Trost and Fleming Comprehensive Organic Synthesis(6 vol.). The skilled artisan will readily appreciate that certainreactions are best carried out when other functionality is masked orprotected in the molecule, thus avoiding any undesirable side reactionsand/or increasing the yield of the reaction. Often the skilled artisanutilizes protecting groups to accomplish such increased yields or toavoid the undesired reactions. These reactions are found in theliterature and are also well within the scope of the skilled artisan.Examples of many of these manipulations are found, for example, in T.Greene, Protecting Groups in Organic Synthesis.

COMPOUND EXAMPLES

The following non-limiting examples provide details for the synthesis ofguanidinyl heterocycles:

Example 1

(4-Methylbenzimidazol-5-yl)guanidine

A. 2,3-Diamino-6-nitrotoluene. To a solution of 30 g of3-methyl-2,4-dinitroaniline in 750 mL of boiling ethanol is addeddropwise over 90 minutes a solution of 109.6 g of sodium sulfidenonahydrate in 750 mL of water. At the end of the addition, the mixtureis heated to reflux for 30 minutes then poured into ice (2000 g) andallowed to stand until all the ice has melted. The mixture is thenextracted with methylene chloride and the organic layer is dried overmagnesium sulfate and rotary evaporated. The residue is purified byflash column chromatography on silica gel, eluting with methylenechloride to afford 2,3-diamino-6-nitrotoluene as an orange solid.

B. 4-Methyl-5-nitrobenzimidazole. A mixture of 11.8 g of2,3-diamino-6-nitrotoluene, 390 mL of 88% formic acid and 38 mL of 12Nhydrochloric acid is heated to reflux for 1 hour. The resulting mixtureis cooled to room temperature and rotary evaporated. The residue isdiluted with 200 mL of water, then basified with ammonium hydroxide(28-30%). The suspension is extracted with ethyl acetate (3×200 mL). Thecombined extracts are dried over magnesium sulfate and rotary evaporatedto provide 4-methyl-5-nitrobenzimidazole as an orange solid.

C. 1-tert-Butoxycarbonyl-4-methyl-5-nitrobenzimidazole. A suspension of11.2 g of 4-methyl-5-nitrobenzimidazole, 21.58 g ofdi-tert-butyl-dicarbonate, 11.7 mL of triethylamine and 100 mg of4-dimethylamino-pyridine in methanol (800 mL) and ethyl acetate (400 mL)is stirred at room temperature overnight. The mixture is rotaryevaporated and the residue purified by flash column chromatography onsilica gel, eluting with 10% ethyl acetate in hexanes. Theproduct-containing fractions are combined and rotary evaporated toafford a white solid contaminated with a yellow oil. The solid isdissolved in methylene chloride and enough hexane is added to causeprecipitation. The solid is filtered and washed with 50% methylenechloride/hexane. The filtrate is rotary evaporated and the processrepeated until no more clean white solid is obtained by precipitation.The combined solid fractions are dried in vacuo to afford1-tert-butoxycarbonyl-4-methyl-5-nitrobenzimidazole as a white solid.

D. 5-Amino-1-tert-butoxycarbonyl-4-methylbenzimidazole. To a solution of8 g of 1-tert-butoxycarbonyl-4-methyl-5-nitrobenzimidazole in 40 mL ofmethanol and 400 mL of ethyl acetate are added 500 mg ofpalladium-on-carbon (10%) and 7.27 g of ammonium formate. The mixture isstirred at 50° C. for 2 hours, then filtered on Celite, with a methanolwash of the solids. The filtrate is rotary evaporated and the residuepartitioned between water and ethyl acetate. The organic layer is washedwith saturated ammonium chloride, dried over magnesium sulfate, filteredand rotary evaporated to afford pure5-amino-1-tert-butoxycarbonyl-4-methylbenzimidazole as an off-whitesolid.

E.1-(tert-Butyloxycarbonyl)-5-[N²,N³-bis(benzyloxycarbonyl)guanidino]-4-methybenzimidazole.To a solution of 500 mg of5-amino-1-(tert-butoxycarbonyl)-4-methyl-benzimidazole in 20 mL oftetrahydrofuran are added 753 mg of ethylN,N-bis(benzyloxycarbonyl)pseudothiourea and 645 mg of mercuric acetateand the mixture is stirred at room temperature for 1 hour. The resultingsuspension is diluted with ethyl acetate and washed with water followedby brine. The aqueous layers are extracted with ethyl acetate; thecombined organic layers are dried over magnesium sulfate, filtered androtary evaporated. The residue is purified by flash columnchromatography on silica gel, eluting with 50% ethyl acetate/hexanesfollowed by recrystallization from hexanes/methylene chloride to provide927 mg of1-(tert-butyloxycarbonyl)-5-[N²,N³-bis(benzyloxycarbonyl)-guanidino]-4-methybenzimidazoleas a white solid.

F. 5-[N²,N³-Bis(benzyloxycarbonyl)guanidino]-4-methylbenzimidazole. To acold (0° C.) solution of 874 mg of1-(tert-butoxycarbonyl)-5-[N²,N³-bis(benzyloxycarbonyl)guanidino]-4-methylbenzimidazolein 2 mL of methylene chloride is added 2 mL of trifluoroacetic acid. Theresulting solution is stirred at room temperature for 30 minutes, thenrotary evaporated. The residue is purified by flash columnchromatography on silica gel, eluting with 20% methanol/chloroformfollowed by recrystallization from hexanes/methylene chloride to provide573 mg of5-[N²,N³-bis(benzyloxycarbonyl)guanidino]-4-methylbenzimidazole as awhite solid.

G. (4-Methylbenzimidazol-5-yl)guanidine, dihydrochloric acid salt. To asolution of 740 mg of5-[N²,N³-bis(benzyloxycarbonyl)guanidino]-4-methyl-benzimidazole in 20mL of ethanol are added 240 mg of ammonium formate and a catalyticamount of palladium-on-carbon. The resulting suspension is stirred atroom temperature for 10 hours. The reaction mixture is filtered and thefiltrate is rotary evaporated. The residue is dissolved in 25 mL ofmethanol and treated with a slow stream of hydrogen chloride gas forabout 5 minutes. The resulting solution is stirred at room temperaturefor 2 hours and rotary evaporated to give a pale yellow solid. The solidis purified by recrystallization from methanol/ethyl acetate to provide361 mg of (4-methylbenzimidazol-5-yl)guanidine, dihydrochloric acid saltas a yellow solid.

Example 2

(4,7-Dimethylbenzimidazol-5-yl)guanidine

A. 4,7-Dimethylbenzimidazole. A mixture of 5.1 g of2,3-diamino-p-xylene, 200 mL of 88% formic acid and 20 mL of 12Nhydrochloric acid is heated to reflux for 3 hours. The resulting mixtureis cooled to room temperature and rotary evaporated. The residue isdiluted with 100 mL of water, then basified with ammonium hydroxide(28-30%). The suspension is extracted with ethyl acetate (3×100 mL). Thecombined extracts are dried over magnesium sulfate and rotary evaporatedto afford 4,7-dimethylbenzimidazole as a yellow solid.

B. 4,7-Dimethyl-5nitrobenzimidazole. To a cold (ice bath) solution of 1g of 4,7-dimethylbenzimidazole in 8 mL of concentrated sulfuric acid isadded dropwise concentrated nitric acid (0.37 mL), over 50 minutes. Themixture is stirred an additional 30 minutes in the ice bath, then pouredinto a mixture of crushed ice (30 mL) and ammonium hydroxide (30 mL).The resulting mixture is extracted with ethyl acetate. The extract isdried over magnesium sulfate and rotary evaporated to afford4,7-dimethyl-5-nitrobenzimidazole as a dark tan solid.

C. 5-Amino-4,7-dimethylbenzimidazole. To a solution of 1.17 g of4,7-dimethyl-5-nitrobenzimidazole in 150 mL of methanol are added 160 mgof palladium-on-carbon (10%) and 1.31 g of ammonium formate. The mixtureis stirred at room temperature overnight, then filtered on Celite, witha methanol wash of the solids. The filtrate is rotary evaporated and theresidue partitioned between water and ethyl acetate. The organic layeris washed with saturated ammonium chloride, dried over magnesiumsulfate, filtered and rotary evaporated to afford5-amino-4,7-dimethylbenzimidazole as a foamy reddish solid.

D. 5-[N²,N³-bis(benzyloxycarbonyl)guanidino]-4,7-dimethybenzimidazole.To a solution of 430 mg of 5-amino-4,7-dimethylbenzimidazole in 100 mLof ethyl acetate and 10 mL of methanol are added 1 g of ethylN,N-bis(benzyloxycarbonyl)pseudothiourea and 855 mg of mercuric acetateand the mixture is stirred at room temperature for 15 hours. The mixtureis rotary evaporated and the residue is purified by flash columnchromatography on silica gel, eluting with 5% methanol/ethyl acetate toprovide 1.01 g of5-[N²,N³-bis(benzyloxycarbonyl)guanidino]-4,7-dimethybenzimidazole as aglassy solid.

E. (4,7-Dimethylbenzimidazol-5-yl)guanidine, dihydrobromic acid salt. Toa solution of 1 g of5-[N²,N³-bis(benzyloxycarbonyl)guanidino]-4,7-dimethyl-benzimidazole in100 mL of 1/1 ethyl acetate/methanol is added a catalytic amount ofpalladium-on-carbon. The resulting suspension is stirred at roomtemperature under hydrogen at atmospheric pressure for 15 hours. Thereaction mixture is filtered on Celite with a methanol wash of thesolids and the filtrate is rotary evaporated. The residue is dissolvedin 50 mL of methanol and treated with 0.85 mL of 30% hydrobromicacid/acetic acid for about 5 minutes. The resulting solution is rotaryevaporated and the residue is purified by recrystallization fromethanol/ether to provide 490 mg of(4,7-dimethylbenzimidazol-5-yl)guanidine dihydrobromic acid salt as awhite solid.

Example 3

(2,4-Dimethylbenzimidazol-5-yl)guanidine

A. 2,4-Dimethyl-5-nitrobenzimidazole. A mixture of 668 mg of2,3-diamino-6-nitrotoluene, 20 mL of glacial acetic acid and 2 mL of 12Nhydrochloric acid is heated to reflux for 3 hours. The resulting mixtureis cooled to room temperature and rotary evaporated. The residue isdiluted with 20 mL of water, and basified with ammonium hydroxide(28-30%). The resulting suspension is extracted with ethyl acetate andthe extracts are dried over magnesium sulfate, filtered and rotaryevaporated to provide 720 mg of 2,4-dimethyl-5-nitrobenzimidazole as atan solid.

B. 5-Amino-2,4-dimethylbenzimidazole. To a solution of 700 mg of2,4-dimethyl-5-nitrobenzimidazole in 50 mL of methanol is added acatalytic amount of palladium-on-carbon. The resulting suspension isstirred at room temperature under hydrogen at atmospheric pressure for15 hours. The reaction mixture is filtered on Celite with a methanolwash of the solids and the filtrate is concentrated. The residue ispurified by flash column chromatography on silica gel, eluting with 5%methanol/ethyl acetate to provide 565 mg of5-amino-2,4-dimethybenzimidazole as a tan solid.

C. (2,4-Dimethylbenzimidazol-5-yl)guanidine, dihydrochloric acid salt.To 565 mg of 5-amino-2,4-dimethylbenzimidazole is added 0.75 mL ofconcentrated hydrochloric acid and 0.38 mL of water. The resultingmixture is stirred at room temperature for 5 minutes to give ahomogeneous paste. To this mixture are added 589 mg of cyanamide and themixture is stirred at 70° C. for 3 hours. The reaction mixture is cooledto 0° C. and 1 mL of water and 0.5 mL of concentrated hydrochloric acidare added. The mixture is stirred at 0° C. for 30 minutes and rotaryevaporated. The residue is dissolved in 10 mL of methanol andprecipitated with ether to provide 594 mg of(2,4-dimethylbenzimidazol-5-yl)guanidine, dihydrochloric acid salt as awhite solid.

Example 4

(1,4-Dimethylbenzimidazol-5-yl)guanidine

A. 2,4-Dinitro-3-methyl-formanilide. To a solution of 2 g of2,4-dinitro-3-methylaniline in 10 mL of 99% formic acid heated at 55°C., are added dropwise 2.5 mL of acetic anhydride, over 15 minutes. Themixture is stirred for 1 hour at 55° C. then cooled to room temperatureand rotary evaporated. The residue is diluted with 100 mL of ethylacetate, washed with saturated aqueous sodium bicarbonate, dried overmagnesium sulfate and rotary evaporated. The residue is purified byflash column chromatography on silica gel, eluting with chloroform, toafford 2,4-dinitro-3-methyl-formanilide as a white solid.

C. N,3-Dimethyl-2,4-dinitroaniline. To a solution of 1.15 g of2,4dinitro-3-methyl-formanilide in 40 mL of dry tetrahydrofuran areadded 1.21 mL of borane-dimethyl sulfide complex. The mixture is heatedto reflux for 2 hours, then cooled in an ice bath; 30 mL of methanol areadded and the stirring is maintained for 1 hour at 0° C. The mixture isacidified to pH=2 with concentrated hydrochloric acid and heated toreflux for 1 hour, diluted with 70 mL of methanol and rotary evaporated.The solid residue is suspended in 150 mL of water and basified to pH=12with concentrated sodium hydroxide. The mixture is extracted withchloroform, and the organic layer is dried over potassium carbonate androtary evaporated. The residue is purified by flash columnchromatography on silica gel, eluting with 25% ethyl acetate/hexane toafford N,3dimethyl-2,4-dinitroaniline as an orange solid.

D. N,3-Dimethyl-2,4-dinitroformanilide. To a solution of 450 mg ofN,3-dimethyl-2,4-dinitroaniline in 10 mL of 99% formic acid and 4 mL ofchloroform heated to 55° C., is added dropwise 1 mL of acetic anhydridein two portions at 1 hour intervals. The mixture is stirred for 5 hoursat 55° C., then cooled to room temperature, poured into 50 mL of 1Nsodium hydroxide and basified to pH=12 with concentrated sodiumhydroxide. The mixture is extracted with methylene chloride, and theorganic layer is dried over magnesium sulfate and rotary evaporated. Theresidue is purified by flash column chromatography on silica gel,eluting with chloroform, to afford N,3dimethyl-2,4-dinitroformanilide asa white solid.

E. 2,4-Diamino-N,3-dimethylformanilide. To a solution of 440 mg ofN,3-dimethyl-2,4-dinitroformanilide in 40 mL of 3/1 methanol/ethylacetate are added 95 mg of palladium-on-carbon (10%) and 930 mg ofammonium formate, and the mixture is stirred for 2 hours at roomtemperature. The mixture is filtered on Celite, with a methanol wash ofthe solids, and the filtrate is rotary evaporated. The residue ispartitioned between methylene chloride and water. The aqueous layer isextracted 4 times with methylene chloride. The combined organic layersare dried over magnesium sulfate and rotary evaporated to afford2,4-diamino-N,3-dimethylformanilide as a brown solid.

F. 5-Amino-1,4-dimethylbenzimidazole. A suspension of 240 mg of2,4-diamino-N,3-dimethylformanilide in 10 mL of 2N hydrochloric acid isheated to reflux for 90 minutes. The mixture is diluted with water (50mL), basified with 1N sodium hydroxide and extracted with ethyl acetate.The organic layer is dried over magnesium sulfate and rotary evaporatedto afford 5-amino-1,4-dimethylbenzimidazole.

G. 5-[N²,N³-bis(benzyloxycarbonyl)guanidino]-1,4-dimethybenzimidazole.

To a solution of 250 mg of 5-amino-1,4-dimethylbenzimidazole in 75 mL ofethyl acetate and 10 mL of methanol are added 789 mg of ethylN,N-bis(benzyloxycarbonyl)pseudothiourea and 665 mg of mercuric acetateand the mixture is stirred at room temperature for 15 hours. The mixtureis filtered on Celite and rotary evaporated. The residue is purified byflash column chromatography on silica gel, eluting with 5%methanol/ethyl acetate to provide 590 mg of5-[N²,N³-bis(benzyloxycarbonyl)guanidino]-1,4-dimethybenzimidazole as awhite solid.

H. (1,4-Dimethylbenzimidazol-5-yl)guanidine, dihydrobromic acid salt. Toa solution of 530 mg of5-[N²,N³-bis(benzyloxycarbonyl)guanidino]-1,4-dimethylbenzimidazole in60 mL of 1/1 ethyl acetate/methanol is added a catalytic amount ofpalladium-on-carbon. The resulting suspension is stirred at roomtemperature under hydrogen at atmospheric pressure for 15 hours. Thereaction mixture is filtered on Celite with a methanol wash of thesolids and the filtrate is rotary evaporated. The residue is dissolvedin 10 mL of methanol and treated with 0.2 mL of 30% hydrobromicacid/acetic acid for about 5 minutes. The resulting solution is rotaryevaporated and the residue is purified by recrystallization usingethanol/ether to provide 30 mg of(1,4-dimethylbenzimidazol-5-yl)guanidine, dihydrobromic acid salt as awhite solid.

Example 5

(4-Bromobenzimidazol-5-yl)gauanidine

A. 5-Amino-4-bromobenzimidazole. To a solution of 1.08 g of5-aminobenzimidazole in 20 mL of glacial acetic acid are added 2.68 g ofsodium acetate. To this solution is added dropwise 0.4 mL of bromine.The resulting brown precipitate is stirred at room temperature for 2hours. The reaction mixture is rotary evaporated and the residue isdiluted with water and ethyl acetate. The mixture is basified with 1Nsodium hydroxide and decanted. The organic layer is washed with waterfollowed by brine. The aqueous layers are extracted with ethyl acetate;the combined organic layers are dried over magnesium sulfate, filteredand rotary evaporated. The residue is purified by flash columnchromatography on silica gel, eluting with 12.5 to 16.5%methanol/methylene chloride followed by recrystallization fromhexanes/ethyl acetate to provide 887 mg of 5-amino-4-bromobenzimidazoleas a pale brown solid.

B. (4-Bromobenzimidazol-5-yl)guanidine, dihydrochloric acid salt. To 637mg of 5-amino-4-bromobenzimidazole are added 0.5 mL of concentratedhydrochloric and 0.25 mL of water. The resulting mixture is stirred atroom temperature for 5 minutes to give a homogeneous paste. To thismixture are added 531 mg of cyanamide and the mixture is stirred at 80°C. for 1 hour. The reaction mixture is cooled to 0° C. and 0.5 mL ofwater and 1 mL of concentrated hydrochloric acid are added. The mixtureis stirred at 0° C. for 30 minutes and rotary evaporated. The residue isdissolved in hot methanol and precipitated using hot ethyl acetate toprovide 766 mg of (4-bromobenzimidazol-5-yl)guanidine, dihydrochloricacid salt as an off-white solid.

Example 6

N¹-Methyl-N²-(4-methylbenzimidazol-5-yl)guanidine

A.1-(tert-Butyloxycarbonyl)-5-[N²,N³-bis(benzyloxycarbonyl)-N²-methylguanidino]-4-methylbenzimidazole.To a solution of 600 mg of5-amino-1-(tert-butoxycarbonyl)-4-methylbenzoimidazole in 20 mL oftetrahydrofuran are added 938 mg of ethylN,N-bis(benzyloxycarbonyl)-N-methylpseudothiourea and 773 mg of mercuricacetate and the mixture is stirred at room temperature for 1 hour. Thesuspension is diluted with ethyl acetate and washed with water followedby brine. The aqueous layers are extracted with ethyl acetate; thecombined organic layers are dried over magnesium sulfate, filtered androtary evaporated. The residue is purified by flash columnchromatography on silica gel, eluting with 50% ethyl acetate/hexanesfollowed by recrystallization from hexanes/methylene chloride to provide927 mg of1-(tert-butyloxycarbonyl)-5-[N²,N³-bis(benzyloxycarbonyl)-N²-methylguanidino]-4-methylbenzimidazoleas a white solid.

B. N¹-Methyl-N²-(4-methylbenzimidazol-5-yl)guanidine, dihydrochloricacid salt. To a solution of 399 mg of5-[N²,N³-bis(benzyloxycarbonyl)-N²-methylguanidino]-4-methylbenzimidazolein 10 mL of ethanol are added 160 mg of ammonium formate and a catalyticamount of palladium-on-carbon. The resulting suspension is heated toreflux for 5 hours. The reaction mixture is filtered on Celite and thefiltrate is rotary evaporated. The residue is dissolved in 2 mL ofmethanol and 0.5 mL of concentrated hydrochloric acid is added. After 5minutes, the mixture is rotary evaporated and dried under vacuum. Theresidue is purified by recrystallization using methanol/ethyl acetate toprovide 211 mg of N¹-Methyl-N²-(4-methylbenzimidazol-5-yl)guanidine,dihydrochloric acid salt as a solid.

Example 7

8-(Methylquinolin-7-yl)guanidine

A. 8-Methyl-7-nitroquinoline. To a suspension of 2 g of2-methyl-3-nitroaniline and 1.02 g of arsenic(v) oxide hydrate are added2.88 mL of glycerin followed by 1.09 mL of concentrated sulfuric acid.The resulting black slurry is stirred at about 150° C. for 4 hours. Theblack oil is cooled to room temperature, diluted with water and pouredinto a mixture of 25% aqueous ammonium hydroxide and ethyl acetate. Theorganic layer is washed with water followed by brine. The aqueous layersare extracted with ethyl acetate; the combined organic layers are driedover magnesium sulfate, filtered and rotary evaporated. The residue ispurified by flash column chromatography on silica gel, eluting with 50%ethyl acetate/hexanes followed by recrystallization fromhexanes/methylene chloride to provide 1.45 g of8-methyl-7-nitroquinoline as a pale brown solid.

B. 7-Amino-8-methylquinoline. To a solution of 1.45 g of8-methyl-7-nitroquinoline in 20 mL of ethanol are added 1.45 g ofammonium formate and a catalytic amount of palladium-on-carbon. Theresulting suspension is stirred at room temperature for 3 hours. Thereaction mixture is filtered on Celite and the filtrate is rotaryevaporated. The residue is purified by flash column chromatography onsilica gel, eluting with 50% ethyl acetate/hexanes followed byrecrystallization from hexanes/methylene chloride to provide 1.10 g of7-amino-8-methylquinoline as a pale yellow solid.

C. 7-[N²,N³-Bis(benzyloxycarbonyl)guanidino]-8-methylquinoline. To apale yellow solution of 500 mg of 7-amino-8-methylquinoline in 20 mL oftetrahydrofuran are added 1.18 g of ethylN,N-bis(benzyloxy-carbonyl)pseudothiourea and 1.01 g of mercuric acetateand the mixture is stirred at room temperature for 1 hour. Thesuspension is diluted with ethyl acetate and the organic layer is washedwith water followed by brine. The aqueous layers are extracted withethyl acetate; the combined organic layers are dried over magnesiumsulfate, filtered and rotary evaporated. The residue is purified byflash column chromatography on silica gel, eluting with 50% ethylacetate/hexanes and recrystallization from hexanes/methylene chloride toprovide 1.257 g of7-[N²,N³-bis(benzyloxycarbonyl)guanidino]-8-ethylquinoline as a whitesolid.

D. 8-(Methylquinolin-7-yl)guanidine, dihydrochloric acid salt. To asolution of 1.25 g of7-[N²,N³-bis(benzyloxycarbonyl)guanidino]-8-methylquinoline in 40 mL ofethanol are added 672 mg of ammonium formate and a catalytic amount ofpalladium-on-carbon. The resulting suspension is stirred at roomtemperature for 10 hours. The reaction mixture is filtered on Celite andthe filtrate is rotary evaporated. The residue is dissolved in 25 mL ofmethanol and treated with a slow stream of hydrogen chloride gas forabout 5 minutes. The resulting solution is stirred at room temperaturefor 2 hours and rotary evaporated to give a pale yellow solid that ispurified by recrystallization from methanol/ethyl acetate to provide 313mg of 8-(methylquinolin-7-yl)guanidine, dihydrochloric acid salt as ayellow solid.

Example 8

(8-Bromoquinolin-7-yl)guanidine

A. 7-Amino-8-bromoquinoline. To a solution of 401 mg of 7-aminoquinolinein 15 mL of glacial acetic acid are added 913 mg of sodium acetatefollowed by a solution of 0.14 mL of bromine in 5 mL of glacial aceticacid. The resulting yellow slurry is stirred at room temperature for 2hours. The brown mixture is rotary evaporated and the residue is dilutedwith water and ethyl acetate. The mixture is basified using 1 N sodiumhydroxide and decanted. The organic layer is washed with water followedby brine. The combined aqueous layers are extracted with ethyl acetate;the combined organic layers are dried over magnesium sulfate and rotaryevaporated. The residue is purified by flash column chromatography onsilica gel, eluting with 20% to 50% ethyl acetate/hexanes followed byrecrystallization from hexanes/methylene chloride to provide 521 mg of7-amino-8-bromoquinoline as a pale brown solid.

B. 7-[N²,N³-Bis(tert-butoxycarbonyl)guanidino]-8-bromoquinoline. To apale yellow solution of 0.40 g of 7-amino-8-bromoquinoline in 10 mL oftetrahydrofuran are added 1.11 g of ethyl N,N-bis(tert-butoxycarbonyl)pseudothiourea and 1.16 g of mercuric acetate and the mixtureis stirred at room temperature for 26 hours. The suspension is dilutedwith ethyl acetate and washed with water followed by brine. The aqueouslayers are extracted with ethyl acetate; the combined organic layers aredried over magnesium sulfate and rotary evaporated. The residue ispurified by flash column chromatography on silica gel, eluting with 15%ethyl acetate/hexanes to provide 0.78 g of7-[N²,N³-bis(tert-butoxycarbonyl)guanidino]-8-bromoquinoline as a whitesolid.

C. (8-Bromoquinolin-7-yl)guanidine, hydrochloric acid salt. To a cold(0° C.) solution of 0.735 g of7-[N²,N³-bis(tert-butoxy-carbonyl)guanidino]-8-bromoquinoline in 2 mL ofmethylene chloride are added 2 mL of trifluoroacetic acid. The resultingsolution is stirred at room temperature for 3 hours and rotaryevaporated to a viscous oil. The oil is dissolved in 10 mL of methanoland 0.5 mL of concentrated hydrochloric acid is added. After 5 minutes,the solution is rotary evaporated and dried under vacuum. The solidresidue is recrystallized from methanol/ethyl acetate to provide 0.41 gof (8-bromoquinolin-7-yl)guanidine, hydrochloric acid salt as a yellowsolid.

Example 9

(6-Methylbenzothiazol-5-yl)guanidine

A. 6-Methyl-5-nitrobenzothiazole. A mixture of 1.6 g of5-chloro-2,4-dinitrotoluene and 20 mL of N,N-dimethyl-thioformamide isheated to 120° C. for 16 hours. After cooling to room temperature, themixture is purified by flash column chromatography on silica gel,eluting with 3% to 10% ethyl acetate/hexanes to provide 0.78 g of6-methyl-5-nitrobenzothiazole as a yellow solid.

B. 5-Amino-6-methylbenzothiazole. A mixture of 0.78 g of6-methyl-5-nitrobenzothiazole and 3.62 g of stannous chloride dihydratein 25 mL of ethanol is heated to 65° C. for 4 hours. The cooled reactionmixture is poured into 10 mL of 50% sodium hydroxide and 45 mL of brineand extracted with ether (4×35 mL). The combined organic layers arewashed with brine, dried over sodium sulfate and rotary evaporated. Theresidue is purified by flash column chromatography on silica gel,eluting with 15% ethyl acetate/hexanes to provide 0.45 g of5-amino-6-methylbenzothiazole as a yellow solid.

C. 5-[N²,N³-Bis(benzyloxycarbonyl)guanidino]-6-methylbenzothiazole. To asolution of 230 mg of 5-amino-6-methylbenzothiazole in 10 mL of 1/1ethyl acetate/methanol are added 520 mg of ethylN,N-bis(benzyloxycarbonyl)-pseudothiourea and 450 mg of mercuric acetateand the mixture is stirred at room temperature for 24 hours. The mixtureis filtered on Celite and rotary evaporated. The residue is purified byflash column chromatography on silica gel, eluting with 20% ethylacetate/hexanes to provide 598 mg of5-[N²,N³-bis(benzyloxycarbonyl)guanidino]-6-methybenzothiazole as ayellow solid.

D. (6-Methylbenzothiazol-5-yl)guanidine, trihydrobromic acid salt. To asolution of 0.58 g of5-[N²,N³-bis(benzyloxycarbonyl)guanidino]-6-methylbenzothiazole in 25 mLof 1/1 methanol/ethyl acetate is added 1 g of 10% palladium-on-carbon.The mixture is stirred under hydrogen at atmospheric pressure for 3days. The mixture is filtered on Celite and rotary evaporated. Theresidue is dissolved into a minimum amount of ethanol and is treatedwith 0.6 mL of 30% hydrobromic acid/acetic acid. Ethyl acetate is addeddropwise to the point of cloudiness and the mixture is stored in thefreezer until crystallization occurs. The solid is filtered and driedunder vacuum to provide 96 mg of (6-methylbenzothiazol-5-yl)guanidine,trihydrobromic acid salt as a white solid.

Example 10

(4-Bromobenzothiazol-5-yl)guanidine

A. 5-Nitrobenzothiazole. A mixture of 10 g of1-chloro-2,4-dinitrobenzene and 20.26 g of N,N-dimethylthioformamide isheated to 60° C. for 3 hours. The resulting solid is suspended in 25 mLof xylene and the mixture is heated to reflux for 4 hours. The mixtureis allowed to cool to room temperature and 15 mL of ethanol are added.The resulting suspension is filtered, and the brown solid is washed witha minimum amount of ethanol. The solid is dissolved in 120 mL ofethanol, heated to boiling, and filtered hot to remove trace solids.After reduction of the volume to about 100 mL, the solution is allowedto stand overnight at room temperature. The resulting solid is filteredand washed with ethanol to provide 4.68 g of 5-nitrobenzothiazole asreddish-brown needles.

B. 5-Aminobenzothiazole. A mixture of 3.46 g of 5-nitrobenzothiazole and15.7 g of stannous chloride dihydrate in 55 mL of 2-propanol is heatedto reflux for 3 hours. The cooled reaction mixture is poured into 150 mLof ice/water and neutralized to pH 7 using solid sodium hydroxide. Themixture is extracted with ethyl acetate (3×50 mL). The combined organiclayers are dried over sodium sulfate, filtered through a short pad ofsilica gel, and rotary evaporated to provide 2.45 g of5-aminobenzothiazole as a yellow-brown solid.

C. 5-Amino-4-bromobenzothiazole. To a cooled (5° C.) solution of 2.04 gof 5-aminobenzothiazole in 60 mL of chloroform are added dropwise 2.15 gof bromine while maintaining the temperature below 10° C. Aftercompletion of the addition, the reaction mixture is stirred for 30minutes at room temperature, then diluted with 14 mL of concentratedammonium hydroxide and 16 mL of methylene chloride. The aqueous layer iswashed with methylene chloride (2×16 mL) and the combined organic layersare rotary evaporated. The residue is purified by an aspiratorvacuum-filtration through silica gel, eluting with 15% to 30 ethylacetate in hexanes to provide 2.44 g of 5-amino-4-bromobenzothiazole asa reddish solid.

D. (4-Bromobenzothiazol-5-yl)guanidine, hydrochloric acid salt. Amixture of 100 mg of 5-amino-4-bromobenzothiazole, 0.05 mL of water and0.097 mL of concentrated hydrochloric acid is stirred at roomtemperature for 5 minutes. To this mixture are added 74 mg of cyanamideand the new mixture is stirred for 90 minutes at 70° C. The reactionmixture is cooled to 0° C. and 0.194 mL of water and 0.098 mL ofconcentrated hydrochloric acid are added. The mixture is stirred for 30minutes at 0° C. and rotary evaporated. The residue is diluted with 1 mLof methanol and precipitated with ether to provide 41 mg of(4-bromobenzothiazol-5-yl)guanidine, hydrochloric acid salt as a whitesolid.

Example 11

N,N′-Dimethyl-(8-methylquinolin-7-yl)guanidine

A. Methyl N,N′-dimethylthiopseudourea. N,N′-Dimethylthioguanidine (5.0g) is added to absolute ethanol (40 mL) while stirring. Methyl iodide(4.3 ml, 1.4 Eq) is rapidly added. The reaction mixture is warmed to30-35° C. for 45 minutes. This solution is used directly in the nextreaction.

B. Methyl N-carbomethoxy-N,N′-dimethylthiopseudourea. Potassiumcarbonate (10.1 g) is added to the mixture in (A) above, followed byaddition of methyl chloroformate (4.2 mL) while stirring. After 45minutes, the reaction mixture is heated to 55° C. and the insolublesalts are filtered off. These salts are washed with 10 mL of absoluteethanol. The filtrate (and ethanol wash) is cooled to −20° C. and therecrystallized product is isolated on a Buchner funnel. The product iswashed with 10 mL cold (−20° C.) absolute ethanol. The product is driedovernight under vacuum at room temperature, yielding methylN-carbomethoxy-N,N′-dimethylthiopseudourea.

C. N,N′-Dimethyl-(8-methylquinolin-7-yl)guanidine. The methylN-carbomethoxy-N,N′-dimethylthiopseudourea is combined with8-methyl-7-nitroquinoline, as prepared in Example 7B, in 10% acetic acidin ethanol and heated to reflux. After the starting amine is consumed,the mixture is decolorized with carbon. The mixture is cooled, filteredand rotary evaporated. Upon recrystallization and drying,N,N′-dimethyl-(8-methylquinolin-7-yl)guanidine is obtained as an aceticacid salt.

Using the methodologies outlined and exemplified above the followingcompounds are made. In these examples where R₁ is nil, (a) is a doublebond, and guanidinyl is signified by GNDNL;

Ex- am- ple R₁ D B R₄ R₅ R₆ R₇ In the following table, R₁₀ = R₁₁ =hydrogen. 12 nil CH NH Cl H GNDNL Me 13 nil CH NH Br H GNDNL Me 14 nilCH NH I H GNDNL Me 15 nil CH NH F H GNDNL Me 16 nil CH NH OMe H GNDNL Me17 nil CH NH CN H GNDNL Me 18 nil CH NH Cl H GNDNL Br 19 nil CH NH Br HGNDNL Br 20 nil CH NH I H GNDNL Br 21 nil CH NH F H GNDNL Br 22 nil CHNH OMe H GNDNL Br 23 nil CH NH Me H GNDNL Br 24 nil CH NH CN H GNDNL Br25 nil CH NH Cl H GNDNL Cl 26 nil CH NH Br H GNDNL Cl 27 nil CH NH I HGNDNL Cl 28 nil CH NH F H GNDNL Cl 29 nil CH NH OMe H GNDNL Cl 30 nil CHNH Me H GNDNL Cl 31 nil CH NH CN H GNDNL Cl 32 nil CH NH H H GNDNL Cl 33nil CH NH Cl H GNDNL OMe 34 nil CH NH Br H GNDNL OMe 35 nil CH NH I HGNDNL OMe 36 nil CH NH F H GNDNL OMe 37 nil CH NH OMe H GNDNL OMe 38 nilCH NH Me H GNDNL OMe 39 nil CH NH CN H GNDNL OMe 40 nil CH NH H H GNDNLOMe 41 nil CH NH Cl H GNDNL SMe 42 nil CH NH Br H GNDNL SMe 43 nil CH NHI H GNDNL SMe 44 nil CH NH F H GNDNL SMe 45 nil CH NH OMe H GNDNL SMe 46nil CH NH Me H GNDNL SMe 47 nil CH NH CN H GNDNL SMe 48 nil CH NH H HGNDNL SMe 49 nil CHMe NH H H GNDNL Et 50 nil CHMe NH H H GNDNL OMe 51nil CH S H H GNDNL Me 52 nil CH S Me H GNDNL Me 53 nil CH S OMe H GNDNLMe 54 nil CH S Br H GNDNL Me 55 nil CH S Cl H GNDNL Me 56 nil CH S F HGNDNL Me 57 nil CH S I H GNDNL Me 58 nil CH S CN H GNDNL Me 59 nil CH SMe H GNDNL Br 60 nil CH S OMe H GNDNL Br 61 nil CH S Br H GNDNL Br 62nil CH S Cl H GNDNL Br 63 nil CH S F H GNDNL Br 64 nil CH S I H GNDNL Br65 nil CH S CN H GNDNL Br 66 nil CH S H OMe GNDNL H 67 nil CH S H BrGNDNL H 68 nil CH S H Me GNDNL Me 69 nil CH S H OMe GNDNL Me 70 nil CH SH Br GNDNL Me 71 nil CH S H Me GNDNL Et 72 nil CH S H OMe GNDNL Et 73nil CH S H Br GNDNL Et 74 nil CH S H Me GNDNL Br 75 nil CH S H OMe GNDNLBr 76 nil CH S H Br GNDNL Br 77 nil CH S H Me GNDNL OMe 78 nil CH S HOMe GNDNL OMe 79 nil CH S H Br GNDNL OMe 80 nil CH S H Me GNDNL SMe 81nil CH S H OMe GNDNL SMe 82 nil CH S H Br GNDNL SMe 83 H CH═ ═CH H HGNDNL Me 84 H CH═ ═C(Br) H H GNDNL Me 85 H CH₂ CH₂ H H GNDNL Me 86 H N══CH H H GNDNL Me 87 H N═ ═CH H H GNDNL Et 88 H N═ ═CH H H GNDNL Br 89nil CH O H H GNDNL Me 90 nil CH CH═CH Cl H GNDNL Me 91 nil CH CH═CH Br HGNDNL Me 92 nil CH CH═CH I H GNDNL Me 93 nil CH CH═CH F H GNDNL Me 94nil CH CH═CH OMe H GNDNL Me 95 nil CH CH═CH Me H GNDNL Me 96 nil CHCH═CH CN H GNDNL Me 97 nil CH CH═CH Cl H GNDNL Br 98 nil CH CH═CH Br HGNDNL Br 99 nil CH CH═CH I H GNDNL Br 100 nil CH CH═CH F H GNDNL Br 101nil CH CH═CH OMe H GNDNL Br 102 nil CH CH═CH Me H GNDNL Br 103 nil CHCH═CH CN H GNDNL Br 104 nil CH CH═CH Cl H GNDNL Cl 105 nil CH CH═CH Br HGNDNL Cl 106 nil CH CH═CH I H GNDNL Cl 107 nil CH CH═CH F H GNDNL Cl 108nil CH CH═CH OMe H GNDNL Cl 109 nil CH CH═CH Me H GNDNL Cl 110 nil CHCH═CH CN H GNDNL Cl 111 nil CH CH═CH H H GNDNL Cl 112 nil CH CH═CH H MeGNDNL Me 113 nil CH CH═CH H Me GNDNL Br 114 nil CH CH═CH H Me GNDNL Cl115 nil CH CH═CH H Me GNDNL OMe 116 nil CH CH═CH H Me GNDNL SMe 117 nilCH CH═CH H OMe GNDNL Me 118 nil CH CH═CH H OMe GNDNL Br 119 nil CH CH═CHH OMe GNDNL Cl 120 nil CH CH═CH H OMe GNDNL OMe 121 nil CH CH═CH H OMeGNDNL SMe 122 nil CH CH═CH H SMe GNDNL Me 123 nil CH CH═CH H SMe GNDNLBr 124 nil CH CH═CH H SMe GNDNL Cl 125 nil CH CH═CH H SMe GNDNL OMe 126nil CH CH═CH H SMe GNDNL SMe 127 nil CH CH═CH H Br GNDNL Me 128 nil CHCH═CH H Br GNDNL Br 129 nil CH CH═CH H Br GNDNL Cl 130 nil CH CH═CH H BrGNDNL OMe 131 nil CH CH═CH H Br GNDNL SMe 132 nil CH CH═CH H C1 GNDNL Me133 nil CH CH═CH H Cl GNDNL Cl 134 nil CH CH═CH Me Me GNDNL Me 135 nilCH CH═CH Me Cl GNDNL Me 136 nil CH CH═CH Me Br GNDNL Me 137 nil CH CH═CHMe I GNDNL Me 138 nil CH CH═CH Me GNDNL H Cl 139 nil CH CH═CH Me GNDNL HBr 140 nil CH CH═CH Me GNDNL H I 141 nil CH CH═CH Me GNDNL H Me 142 nilCH CH═CH Et GNDNL H Cl 143 nil CH CH═CH Et GNDNL H Br 144 nil CH CH═CHEt GNDNL H I 145 nil CH CH═CH Et GNDNL H Me 146 nil CH CH═CH Br GNDNL HCl 147 nil CH CH═CH Br GNDNL H Br 148 nil CH CH═CH Br GNDNL H I 149 nilCH CH═CH Br GNDNL H Me 150 nil CH CH═CH Cl GNDNL H Cl 151 nil CH CH═CHCl GNDNL H Br 152 nil CH CH═CH Cl GNDNL H I 153 nil CH CH═CH Cl GNDNL HMe 154 nil CH CH═CH OMe GNDNL H Cl 155 nil CH CH═CH OMe GNDNL H Br 156nil CH CH═CH OMe GNDNL H I 157 nil CH CH═CH OMe GNDNL H Me 158 nil CHCH═CH SMe GNDNL H Cl 159 nil CH CH═CH SMe GNDNL H Br 160 nil CH CH═CHSMe GNDNL H I 161 nil CH CH═CH SMe GNDNL H Me 162 nil CH CH═CH Me GNDNLMe H 163 nil CH CH═CH Me GNDNL Br H 164 nil CH CH═CH Me GNDNL Cl H 165nil CH CH═CH Me GNDNL OMe H 166 nil CH CH═CH Me GNDNL SMe H 167 nil CHCH═CH Et GNDNL Me H 168 nil CH CH═CH Et GNDNL Br H 169 nil CH CH═CH EtGNDNL Cl H 170 nil CH CH═CH Et GNDNL OMe H 171 nil CH CH═CH Et GNDNL SMeH 172 nil CH CH═CH Br GNDNL Me H 173 nil CH CH═CH Br GNDNL Br H 174 nilCH CH═CH Br GNDNL Cl H 175 nil CH CH═CH Br GNDNL OMe H 176 nil CH CH═CHBr GNDNL SMe H 177 nil CH CH═CH Cl GNDNL Me H 178 nil CH CH═CH Cl GNDNLBr H 179 nil CH CH═CH Cl GNDNL Cl H 180 nil CH CH═CH Cl GNDNL OMe H 181nil CH CH═CH Cl GNDNL SMe H 182 nil CH CH═CH OMe GNDNL Me H 183 nil CHCH═CH OMe GNDNL Br H 184 nil CH CH═CH OMe GNDNL Cl H 185 nil CH CH═CHOMe GNDNL OMe H 186 nil CH CH═CH OMe GNDNL SMe H 187 nil CH CH═CH SMeGNDNL Me H 188 nil CH CH═CH SMe GNDNL Br H 189 nil CH CH═CH SMe GNDNLOMe H 190 nil CH CH═CH SMe GNDNL SMe H 191 nil CH CH═CH Me GNDNL Me Me192 nil CH C(Me)═CH Me GNDNL H Me 193 nil CH C(Br)═CH Me GNDNL H Me 194nil CH C(Cl)═CH Me GNDNL H Me 195 nil CH C(F)═CH Me GNDNL H Me 196 nilCH CH═C(Me) Me GNDNL H Me 197 nil CH CH═C(CN) Me GNDNL H Me 198 nil CHCH═C(Br) Me GNDNL H Me 199 nil CH CH═C(Cl) Me GNDNL H Me 200 nil CHCH═C(F) Me GNDNL H Me 201 nil CH S Me GNDNL H Me 202 nil CH S Me GNDNL HCl 203 nil CH S Me GNDNL H Br 204 nil CH S Me GNDNL H I 205 nil CH S MeGNDNL H OMe 206 nil CH S Cl GNDNL H Me 207 nil CH S Cl GNDNL H Cl 208nil CH S Cl GNDNL H Br 209 nil CH S Cl GNDNL H I 210 nil CH S Cl GNDNL HOMe 211 nil CH S Br GNDNL H Me 212 nil CH S Br GNDNL H Cl 213 nil CH SBr GNDNL H Br 214 nil CH S Br GNDNL H I 215 nil CH S Br GNDNL H OMe 216nil CH S I GNDNL H Me 217 nil CH S I GNDNL H Cl 218 nil CH S I GNDNL HBr 219 nil CH S I GNDNL H I 220 nil CH S I GNDNL H OMe 221 nil CH S EtGNDNL H Me 222 nil CH S Et GNDNL H Cl 223 nil CH S Et GNDNL H Br 224 nilCH S Et GNDNL H I 225 nil CH S Et GNDNL H OMe 226 nil CH S Me GNDNL Me H227 nil CH S Me GNDNL Cl H 228 nil CH S Me GNDNL Br H 229 nil CH S MeGNDNL I H 230 nil CH S Cl GNDNL Cl H 231 nil CH S Me GNDNL Me Me 232 nilCH S Me GNDNL Cl Me 233 nil CH S Me GNDNL Br Me 234 nil CH S Me GNDNL IMe 235 nil CH S Et GNDNL H Me 236 nil CH S Et GNDNL H Me In thefollowing table, R₁₀ = Me and R₁₁ = H. 237 nil CH NH H H GNDNL Br 238nil CH CH═CH H H GNDNL Me 239 nil CH CH═CH Me GNDNL H Me 240 nil CH S HH GNDNL Me 241 nil CH S H H GNDNL Br In the following table, R₁₀ = Etand R₁₁ = H. 242 nil CH N H H GNDNL Me 243 nil CH CH═CH H H GNDNL Me 244nil CH CH═CH Me GNDNL H Me 245 nil CH S H H GNDNL Me 246 nil CH S H HGNDNL Br

Compositions

Another aspect of this invention is compositions which comprise a safeand effective amount of a subject compound, or apharmaceutically-acceptable salt thereof, and apharmaceutically-acceptable carrier.

As used herein, “safe and effective amount” means an amount of thesubject compound sufficient to significantly induce a positivemodification in the condition to be treated, but low enough to avoidserious side effects (at a reasonable benefit/risk ratio), within thescope of sound medical judgment. A safe and effective amount of thesubject compound will vary with the age and physical condition of thepatient being treated, the severity of the condition, the duration ofthe treatment, the nature of concurrent therapy, the particularpharmaceutically-acceptable carrier utilized, and like factors withinthe knowledge and expertise of the attending physician.

Preparing a dosage form is within the purview of the skilled artisan.Examples are provided for the skilled artisan, but are non-limiting, andit is contemplated that the skilled artisan can prepare variations ofthe compositions claimed.

Compositions of this invention preferably comprise from about 0.0001% toabout 99% by weight of the subject compound, more preferably from about0.01% to about 90% of the compound of the invention. Depending upon theroute of administration and attendant bioavailability, solubility ordissolution characteristics of the dosage form, the dosage form haspreferably from about 10% to about 50%, also preferably from about 5% toabout 10%, also preferably from about 1% to about 5%, and alsopreferably from about 0.01% to about 1% of the subject compound. Thefrequency of dosing of the subject compound is dependent upon thepharmacokinetic properties of each specific agent (for example,biological half-life) and can be determined by the skilled artisan.

In addition to the subject compound, the compositions of this inventioncontain a pharmaceutically-acceptable carrier. The term“pharmaceutically-acceptable carrier”, as used herein, means one or morecompatible solid or liquid filler diluents or encapsulating substanceswhich are suitable for administration to a mammal. The term“compatible”, as used herein, means that the components of thecomposition are capable of being commingled with the subject compound,and with each other, in a manner such that there is no interaction whichwould substantially reduce the pharmaceutical efficacy of thecomposition under ordinary use situations. Preferably when liquid doseforms are used, the compounds of the invention are soluble in thecomponents of the composition. Pharmaceutically-acceptable carriersmust, of course, be of sufficiently high purity and sufficiently lowtoxicity to render them suitable for administration to the mammal beingtreated.

Some examples of substances which can serve aspharmaceutically-acceptable carriers or components thereof are sugars,such as lactose, glucose and sucrose; starches, such as corn starch andpotato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; vegetable oils, such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil and oil oftheobroma; polyols such as propylene glycol, glycerine, sorbitol,mannitol, and polyethylene glycol; alginic acid; emulsifiers, such asthe Tweens®; wetting agents, such sodium lauryl sulfate; coloringagents; flavoring agents; tableting agents, stabilizers; antioxidants;preservatives; pyrogen-free water, isotonic saline; and phosphate buffersolutions. The choice of a pharmaceutically-acceptable carrier to beused in conjunction with the subject compound is basically determined bythe way the compound is to be administered. If the subject compound isto be injected, the preferred pharmaceutically-acceptable carrier issterile, physiological saline, with a blood-compatible suspending agent,the pH of which has been adjusted to about 7.4.

If the preferred mode of administering the subject compound isperorally, the preferred unit dosage form is therefore tablets,capsules, lozenges, chewable tablets, and the like. Such unit dosageforms comprise a safe and effective amount of the subject compound,which is preferably from about 0.01 mg to about 350 mg, more preferablyfrom about 0.1 mg to about 35 mg, based on a 70 kg person. Thepharmaceutically-acceptable carrier suitable for the preparation of unitdosage forms for peroral administration are well-known in the art.Tablets typically comprise conventional pharmaceutically-compatibleadjuvants as inert diluents, such as calcium carbonate, sodiumcarbonate, mannitol, lactose and cellulose; binders such as starch,gelatin and sucrose; disintegrants such as starch, alginic acid andcroscarmelose; lubricants such as magnesium stearate, stearic acid andtalc. Glidants such as silicon dioxide can be used to improve flowcharacteristics of the powder mixture. Coloring agents, such as the FD&Cdyes, can be added for appearance. Sweeteners and flavoring agents, suchas aspartame, saccharin, menthol, peppermint, and fruit flavors, areuseful adjuvants for chewable tablets. Capsules typically comprise oneor more solid diluents disclosed above. The selection of carriercomponents depends on secondary considerations like taste, cost, andshelf stability, which are not critical for the purposes of thisinvention, and can be readily made by a person skilled in the art.

Peroral compositions also include liquid solutions, emulsions,suspensions, and the like. The pharmaceutically-acceptable carrierssuitable for preparation of such compositions are well known in the art.Such liquid oral compositions preferably comprise from about 0.001% toabout 5% of the subject compound, more preferably from about 0.01% toabout 0.5%. Typical components of carriers for syrups, elixirs,emulsions and suspensions include ethanol, glycerol, propylene glycol,polyethylene glycol, liquid sucrose, sorbitol and water. For asuspension, typical suspending agents include methyl cellulose, sodiumcarboxymethyl cellulose, Avicel® RC-591, tragacanth and sodium alginate;typical wetting agents include lecithin and polysorbate 80; and typicalpreservatives include methyl paraben and sodium benzoate. Peroral liquidcompositions may also contain one or more components such as sweeteners,flavoring agents and colorants disclosed above.

Other compositions useful for attaining systemic delivery of the subjectcompounds include sublingual and buccal dosage forms. Such compositionstypically comprise one or more of soluble filler substances such assucrose, sorbitol and mannitol; and binders such as acacia,microcrystalline cellulose, carboxymethyl cellulose and hydroxypropylmethyl cellulose. Glidants, lubricants, sweeteners, colorants,antioxidants and flavoring agents disclosed above may also be included.

Compositions can also be used to deliver the compound to the site whereactivity is desired: intranasal doses for nasal decongestion, inhalantsfor asthma, and eye drops, gels and creams for ocular disorders.

Preferred compositions of this invention include solutions or emulsions,preferably aqueous solutions or emulsions comprising a safe andeffective amount of a subject compound intended for topical intranasaladministration. Such compositions preferably comprise from about 0.001%to about 25% of a subject compound, more preferably from about 0.01% toabout 10%. Similar compositions are preferred for systemic delivery ofsubject compounds by the intranasal route. Compositions intended todeliver the compound systemically by intranasal dosing preferablycomprise similar amounts of a subject compound as are determined to besafe and effective by peroral or parenteral administration. Suchcompositions used for intranasal dosing also typically include safe andeffective amounts of preservatives, such as benzalkonium chloride andthimerosal and the like; chelating agents, such as edetate sodium andothers; buffers such as phosphate, citrate and acetate; tonicity agentssuch as sodium chloride, potassium chloride, glycerin, mannitol andothers; antioxidants such as ascorbic acid, acetylcystine, sodiummetabisulfate and others; aromatic agents; viscosity adjustors, such aspolymers, including cellulose and derivatives thereof, and polyvinylalcohol and acids and bases to adjust the pH of these aqueouscompositions as needed. The compositions may also comprise localanesthetics or other actives. These compositions can be used as sprays,mists, drops, and the like.

Other preferred compositions of this invention include aqueoussolutions, suspensions, and dry powders comprising a safe and effectiveamount of a subject compound intended for atomization and inhalationadministration. Such compositions preferably comprise from about 0.1% toabout 50% of a subject compound, more preferably from about 1% to about20%; of course, the amount can be altered to fit the circumstance of thepatient contemplated and the package. Such compositions are typicallycontained in a container with attached atomizing means. Suchcompositions also typically include propellants such aschlorofluorocarbons 12/11 and 12/114, and more environmentally friendlyfluorocarbons, or other nontoxic volatiles; solvents such as water,glycerol and ethanol, these include cosolvents as needed to solvate orsuspend the active; stabilizers such as ascorbic acid, sodiummetabisulfate; preservatives such as cetylpyridinium chloride andbenzalkonium chloride; tonicity adjustors such as sodium chloride;buffers; and flavoring agents such as sodium saccharin. Suchcompositions are useful for treating respiratory disorders, such asasthma and the like.

Other preferred compositions of this invention include aqueous solutionscomprising a safe and effective amount of a subject compound intendedfor topical intraocular administration. Such compositions preferablycomprise from about 0.0001% to about 5% of a subject compound, morepreferably from about 0.01% to about 0.5%. Such compositions alsotypically include one or more of preservatives, such as benzalkoniumchloride, thimerosal, phenylmercuric acetate; vehicles, such aspoloxamers, modified celluloses, povidone and purified water; tonicityadjustors, such as sodium chloride, mannitol and glycerin; buffers suchas acetate, citrate, phosphate and borate; antioxidants such as sodiummetabisulfite, butylated hydroxy toluene and acetyl cysteine; acids andbases may be used to adjust the pH of these formulations as needed.

Other preferred compositions of this invention useful for peroraladministration include solids, such as tablets and capsules, andliquids, such as solutions, suspensions and emulsions (preferably insoft gelatin capsules), comprising a safe and effective amount of asubject compound. Such compositions preferably comprise from about 0.01mg to about 350 mg per dose, more preferably from about 0.1 mg to about35 mg per dose. Such compositions can be coated by conventional methods,typically with pH or time-dependent coatings, such that the subjectcompound is released in the gastrointestinal tract at various times toextend the desired action. Such dosage forms typically include, but arenot limited to, one or more of cellulose acetate phthalate,polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate,ethyl cellulose, Eudragit® coatings, waxes and shellac.

Any of the compositions of this invention may optionally include otherdrug actives. Non-limiting examples of drug actives which may beincorporated in these compositions, include:

Antihistamines, including:

Hydroxyzine, preferably at a dosage range of from about 25 to about 400mg; Doxylamine, preferably at a dosage range of from about 3 to about 75mg; Pyrilamine, preferably at a dosage range of from about 6.25 to about200 mg; Chlorpheniramine, preferably at a dosage range of from about 1to about 24 mg; Phenindamine, preferably at a dosage range of from about6.25 to about 150 mg; Dexchlorpheniramine, preferably at a dosage rangeof from about 0.5 to about 12 mg; Dexbrompheniramine, preferably at adosage range of from about 0.5 to about 12 mg; Clemastine, preferably ata dosage range of from about 1 to about 9 mg; Diphenhydramine,preferably at a dosage range of from about 6.25 to about 300 mg;Azetastine, preferably at a dosage range of from about 140 to about1,680 μg (when dosed intranasally); 1 to about 8 mg (when dosed orally);Acrivastine, preferably at a dosage range of from about 1 to about 24mg; Levocarbastine (which can be dosed as an intranasal or ocularmedicament), preferably at a dosage range of from about 100 to about 800mg; Mequitazine, preferably at a dosage range of from about 5 to about20 mg; Astemizole, preferably at a dosage range of from about 5 to about20 mg; Ebastine, preferably at a dosage range of from about 5 to about20 mg; Loratadine, preferably at a dosage range of from about 5 to about40 mg; Cetirizine, preferably at a dosage range of from about 5 to about20 mg; Terfenadine, preferably at a dosage range of from about 30 toabout 480 mg; Terfenadine metabolites; Promethazine, preferably at adosage range of from about 6.25 to about 50 mg; Dimenhydrinate,preferably at a dosage range of from about 12.5 to about 400 mg;Meclizine, preferably at a dosage range of from about 6.25 to about 50mg; Tripelennamine, preferably at a dosage range of from about 6.25 toabout 300 mg; Carbinoxamine, preferably at a dosage range of from about0.5 to about 16 mg; Cyproheptadine, preferably at a dosage range of fromabout 2 to about 20 mg; Azatadine, preferably at a dosage range of fromabout 0.25 to about 2 mg; Brompheniramine, preferably at a dosage rangeof from about 1 to about 24 mg; Triprolidine, preferably at a dosagerange of from about 0.25 to about 10 mg; Cyclizine, preferably at adosage range of from about 12.5 to about 200 mg; Thonzylamine,preferably at a dosage range of from about 12.5 to about 600 mg;Pheniramine, preferably at a dosage range of from about 3 to about 75mg; Cyclizine, preferably at a dosage range of from about 12.5 to about200 mg and others;

Antitussives, including:

Codeine, preferably at a dosage range of from about 2.5 to about 120 mg;Hydrocodone, preferably at a dosage range of from about 2.5 to about 40mg; Dextromethorphan, preferably at a dosage range of from about 2.5 toabout 120 mg; Noscapine, preferably at a dosage range of from about 3 toabout 180 mg; Benzonatate, preferably at a dosage range of from about100 to about 600 mg; Diphenhydramine, preferably at a dosage range offrom about 12.5 to about 150 mg; Chlophedianol, preferably at a dosagerange of from about 12.5 to about 100 mg; Clobutinol, preferably at adosage range of from about 20 to about 240 mg; Fominoben, preferably ata dosage range of from about 80 to about 480 mg; Glaucine; Pholcodine,preferably at a dosage range of from about 1 to about 40 mg; Zipeprol,preferably at a dosage range of from about 75 to about 300 mg;Hydromorphone, preferably at a dosage range of from about 0.5 to about 8mg; Carbetapentane, preferably at a dosage range of from about 15 toabout 240 mg; Caramiphen, preferably at a dosage range of from about 10to about 100 mg; Levopropoxyphene, preferably at a dosage range of fromabout 25 to about 200 mg and others;

Antiinflammatories, preferably Non-Steroidal Anti-inflammatories.(NSAIDS) including:

Ibuprofen, preferably at a dosage range of from about 50 to about 3,200mg; Naproxen, preferably at a dosage range of from about 62.5 to about1,500 mg; Sodium naproxen, preferably at a dosage range of from about110 to about 1,650 mg; Ketoprofen, preferably at a dosage range of fromabout 25 to about 300 mg; Indoprofen, preferably at a dosage range offrom about 25 to about 200 mg; Indomethacin, preferably at a dosagerange of from about 25 to about 200 mg; Sulindac, preferably at a dosagerange of from about 75 to about 400 mg; Diflunisal, preferably at adosage range of from about 125 to about 1,500 mg; Ketorolac, preferablyat a dosage range of from about 10 to about 120 mg; Piroxicam,preferably at a dosage range of from about 10 to about 40 mg; Aspirin,preferably at a dosage range of from about 80 to about 4,000 mg;Meclofenamate, preferably at a dosage range of from about 25 to about400 mg; Benzydamine, preferably at a dosage range of from about 25 toabout 200 mg; Carprofen, preferably at a dosage range of from about 75to about 300 mg; Diclofenac, preferably at a dosage range of from about25 to about 200 mg; Etodolac, preferably at a dosage range of from about200 to about 1,200 mg; Fenbufen, preferably at a dosage range of fromabout 300 to about 900 mg; Fenoprofen, preferably at a dosage range offrom about 200 to about 3,200 mg; Flurbiprofen, preferably at a dosagerange of from about 50 to about 300 mg; Mefenamic acid, preferably at adosage range of from about 250 to about 1,500 mg; Nabumetone, preferablyat a dosage range of from about 250 to about 2,000 mg; Phenylbutazone,preferably at a dosage range of from about 100 to about 400 mg;Pirprofen, preferably at a dosage range of from about 100 to about 800mg; Tolmetin, preferably at a dosage range of from about 200 to about1,800 mg and others;

Analgesics, including:

Acetaminophen, preferably at a dosage range of from about 80 to about4,000 mg; and others:

Expectorants/Mucolytics, including:

Guaifenesin, preferably at a dosage range of from about 50 to about2,400 mg; N-Acetylcysteine, preferably at a dosage range of from about100 to about 600 mg; Ambroxol, preferably at a dosage range of fromabout 15 to about 120 mg; Bromhexine, preferably at a dosage range offrom about 4 to about 64 mg; Terpin hydrate, preferably at a dosagerange of from about 100 to about 1,200 mg; Potassium iodide, preferablyat a dosage range of from about 50 to about 250 mg and others;

Anticholinergics (e.g., Atropinics), preferably intranasally or orallyadministered anticholinergics, including:

Ipratroprium (preferably intranasally), preferably at a dosage range offrom about 42 to about 252 μg; Atropine sulfate (preferably oral),preferably at a dosage range of from about 10 to about 1,000 μg;Belladonna (preferably as an extract), preferably at a dosage range offrom about 15 to about 45 mg equivalents; Scopolamine, preferably at adosage range of from about 400 to about 3,200 μg; Scopolaminemethobromide, preferably at a dosage range of from about 2.5 to about 20mg; Homatropine methobromide, preferably at a dosage range of from about2.5 to about 40 mg; Hyoscyamine (preferably oral), preferably at adosage range of from about 125 to about 1,000 μg; Isopropramide(preferably oral), preferably at a dosage range of from about 5 to about20 mg; Orphenadrine (preferably oral), preferably at a dosage range offrom about 50 to about 400 mg; Benzalkonium chloride (preferablyintranasally) preferably a 0.005 to about 0.1% solution and others;

Mast Cell Stabilizers, preferably intranasally, or orally administeredmast cell stabilizers, including:

Cromalyn, preferably at a dosage range of from about 10 to about 60 mg;Nedocromil, preferably at a dosage range of from about 10 to about 60mg; Oxatamide, preferably at a dosage range of from about 15 to about120 mg; Ketotifen, preferably at a dosage range of from about 1 to about4 mg; Lodoxamide, preferably at a dosage range of from about 100 toabout 3,000 μg and others;

Leukotrene Antagonists, including Zileuton and others; Methylxanthines,including:

Caffeine, preferably at a dosage range of from about 65 to about 600 mg;Theophylline, preferably at a dosage range of from about 25 to about1,200 mg; Enprofylline; Pentoxifylline, preferably at a dosage range offrom about 400 to about 3,600 mg; Aminophylline, preferably at a dosagerange of from about 50 to about 800 mg; Dyphylline, preferably at adosage range of from about 200 to about 1,600 mg and others;

Antioxidants or radical inhibitors, including:

Ascorbic add, preferably at a dosage range of from about 50 to about10,000 mg; Tocopherol, preferably at a dosage range of from about 50 toabout 2,000 mg; Ethanol, preferably at a dosage range of from about 500to about 10,000 mg and others;

Steroids, preferably intranasally administered steroids, including:

Beclomethasone, preferably at a dosage range of from about 84 to about336 μg; Fluticasone, preferably at a dosage range of from about 50 toabout 400 μg; Budesonide, preferably at a dosage range of from about 64to about 256 μg; Mometasone, preferably at a dosage range of from about50 to about 300 mg; Triamcinolone, preferably at a dosage range of fromabout 110 to about 440 μg; Dexamethasone, preferably at a dosage rangeof from about 168 to about 1,008 μg; Flunisolide, preferably at a dosagerange of from about 50 to about 300 μg; Prednisone (preferably oral),preferably at a dosage range of from about 5 to about 60 mg;Hydrocortisone (preferably oral), preferably at a dosage range of fromabout 20 to about 300 mg and others;

Bronchodilators, preferably for inhalation, including:

Albuterol, preferably at a dosage range of from about 90 to about 1,080μg; 2 to about 16 mg (if dosed orally); Epinephrine, preferably at adosage range of from about 220 to about 1,320 μg; Ephedrne, preferablyat a dosage range of from about 15 to about 240 mg (if dosed orally);250 to about 1,000 μg (if dosed intranasally); Metaproterenol,preferably at a dosage range of from about 65 to about 780 μg or 10 toabout 80 mg if dosed orally; Terbutaline, preferably at a dosage rangeof from about 200 to about 2,400 μg; 2.5 to about 20 mg (if dosedorally); Isoetharine, preferably at a dosage range of from about 340 toabout 1,360 μg; Pirbuterol, preferably at a dosage range of from about200 to about 2,400 μg; Bitolterol, preferably at a dosage range of fromabout 370 to about 2,220 μg; Fenoterol, preferably at a dosage range offrom about 100 to about 1,200 μg; 2.5 to about 20 mg (if dosed orally);Rimeterol, preferably at a dosage range of from about 200 to about 1,600μg; Ipratroprium, preferably at a dosage range of from about 18 to about216 μg (inhalation) and others; and

Antivirals, including:

Amantadine, preferably at a dosage range of from about 50 to about 200mg; Rimantadine, preferably at a dosage range of from about 50 to about200 mg; Enviroxime; Nonoxinols, preferably at a dosage range of fromabout 2 to about 20 mg (preferably an intranasal form); Acyclovir,preferably at a dosage range of from about 200 to about 2,000 mg (oral);1 to about 10 mg (preferably an intranasal form); Alpha-interferon,preferably at a dosage range of from about 3 to about 36 MIU;Beta-interferon, preferably at a dosage range of from about 3 to about36 MIU and others;

Ocular Drug actives: acetylcholinesterase inhibitors, e.g.,echothiophate from about 0.03% to about 0.25% in topical solution andothers; and

Gastrointestinal actives: antidiarrheals, e.g., Ioperamide from about0.1 mg to about 1.0 mg per dose, and bismuth subsalicylate from about 25mg to about 300 mg per dose and others.

Of course, clearly contemplated and included in the description aboveare the acid or base addition salts, esters, metabolites, stereoisomersand enantiomers of these preferred combination actives, as well as theiranalogues of these actives that are safe and effective. It is alsorecognized that an active may be useful for more than one of the aboveuses, and these uses are clearly contemplated as well. This overlap isrecognized in the art and adjusting dosages and the like to fit theindication is well within the purview of the skilled medicalpractitioner.

Methods of Use

Without being bound by theory, it is contemplated that the primarymechanism by which alpha-2 agonists provide efficacy is by interveningin the biological cascade responsible for disorder(s) and/ormanifestation(s) thereof. It may be that there is no deficit in alpha-2adrenoceptor activity: such activity may be normal. However,administration of an alpha-2 agonist may be a useful way of rectifying adisorder, condition or manifestation thereof.

Thus as used herein, the terms “disease,” “disorder” and “condition” areused interchangeably to refer to maladies related to or modulated byalpha-2 adrenoceptor activity.

As used herein, a disorder described by the terms “modulated by alpha-2adrenoceptors,” or “modulated by alpha-2 adrenoceptor activity” refersto a disorder, condition or disease where alpha-2 adrenoceptor activityis an effective means of alleviating the disorder or one or more of thebiological manifestations of the disease or disorder; or interferes withone or more points in the biological cascade either leading to thedisorder or responsible for the underlying disorder; or alleviates oneor more symptoms of the disorder. Thus, disorders subject to“modulation” include those for which:

The lack of alpha-2 activity is a “cause” of the disorder or one or moreof the biological manifestations, whether the activity was alteredgenetically, by infection, by irritation, by internal stimulus or bysome other cause;

The disease or disorder or the observable manifestation ormanifestations of the disease or disorder are alleviated by alpha-2activity. The lack of alpha-2 acivity need not be causally related tothe disease or disorder or the observable manifestations thereof;

Alpha-2 activity interferes with part of the biochemical or cellularcascade that results in or relates to the disease or disorder. In thisrespect, the alpha-2 activity alters the cascade, and thus controls thedisease, condition or disorder.

The compounds of this invention are particularly useful for thetreatment of nasal congestion associated with allergies, colds, andother nasal disorders, as well as the sequelae of congestion of themucous membranes (for example, sinusitis and otitis media). At effectivedoses, it has been found that undesired side effects can be avoided.

While not limited to a particular mechanism of action, the subjectcompounds are believed to provide advantages in the treatment of nasaldecongestion over related compounds through their ability to interactwith alpha-2 adrenoceptors. The subject compounds have been found to bealpha-2 adrenoceptor agonists which cause constriction of peripheralvascular beds in the nasal turbinates.

Alpha-2 adrenoceptors are distributed both inside and outside of thecentral nervous system. Thus, though not essential for activity orefficacy, certain disorders preferably are treated with compounds thatact on alpha-2 adrenoceptors in only one of these regions. Compounds ofthis invention vary in their ability to penetrate into the centralnervous system and, thus, to produce effects mediated through centralalpha-2 adrenoceptors. Thus, for example, a compound which displays ahigher degree of central nervous system activity is preferred forcentral nervous system indications over other compounds as describedbelow. However, even for compounds that exhibit primarily peripheralactivity, central nervous system actions can be evoked by an increase inthe dose of the compound. Further specificity of action of thesecompounds can be achieved by delivering the agent to the region whereactivity is desired (for example, topical administration to the eye,nasal mucosa or respiratory tract).

Compounds preferred for, but not limited to, the treatment of certaincardiovascular disorders, pain, substance abuse and/or withdrawal, ulcerand hyperacidity include those compounds that are centrally acting. Bycentrally acting what is meant is that they have some action on thealpha-2 adrenoceptors in the central nervous system in addition to theiraction at peripheral alpha-2 adrenoceptors.

Compounds preferred for, but not limited to, the treatment ofrespiratory disorders, ocular disorders, migraine, certaincardiovascular disorders, and certain other gastrointestinal disordersare peripherally acting. By peripherally acting, what is meant is thatthese compounds act primarily on alpha-2 adrenoceptors in the periphery,rather than those in the central nervous system. Methods are availablein the art to determine which compounds are primarily peripherallyacting and which are primarily centrally acting.

Thus, compounds of the subject invention are also useful for thetreatment of ocular disorders such as ocular hypertension, glaucoma,hyperemia, conjunctivitis, and uveitis. The compounds are administeredeither perorally, or topically as drops, sprays, mists, gels or creamsdirectly to the surface of the mammalian eye.

The compounds of this invention are also useful for controllinggastrointestinal disorders, such as diarrhea, irritable bowel syndrome,hyperchlorhydria and peptic ulcer.

The compounds of this invention are also useful for diseases anddisorders associated with sympathetic nervous system activity, includinghypertension, myocardial ischemia, cardiac reperfusion injury, angina,cardiac arrhythmia, heart failure and benign prostatic hypertrophy. Dueto their sympatholytic effect, compounds are also useful as an adjunctto anesthesia during surgical procedures.

The compounds of this invention are also useful for relieving painassociated with various disorders. The compounds are administeredperorally, parenterally, and/or by direct injection into thecerebrospinal fluid.

The compounds of this invention are also useful for the prophylactic oracute treatment of migraine. The compounds are administered perorally,parenterally or intranasally.

The compounds of this invention are also useful for treatment ofsubstance abuse, in particular abuse of alcohol and opiates, andalleviating the abstinence syndromes evoked by withdrawal of thesesubstances.

The compounds of this invention are also useful for other diseases anddisorders where vasoconstriction, particularly of veins, would provide abenefit, including septic or cardiogenic shock, elevated intracranialpressure, hemmorhoids, venous insufficiency, varicose veins, andmenopausal flushing.

The compounds of this invention are also useful for neurologic diseasesand disorders, including spasticity, epilepsy, attention deficithyperactive disorder, Tourette's syndrome, and cognitive disorders.

The pharmacological activity and selectivity of these compounds can bedetermined using published test procedures. The alpha-2 selectivity ofthe compounds is determined by measuring receptor binding affinities andin vitro functional potencies in a variety of tissues known to possessalpha-2 and/or alpha-1 receptors. (See, e.g., The Alpha-2 AdrenergicReceptors, L. E. Limbird, ed., Humana Press, Clifton, N.J.) Thefollowing in vivo assays are typically conducted in rodents or otherspecies. Central nervous system activity is determined by measuringlocomotor activity as an index of sedation. (See, e.g., Spyraki, C. & H.Fibiger, “Clonidine-induced Sedation in Rats: Evidence for Mediation byPostsynaptic Alpha-2 Adrenoreceptors”, Journal of Neural Transmission,Vol. 54 (1982), pp. 153-163). Nasal decongestant activity is measuredusing rhinomanometry as an estimate of nasal airway resistance. (See,e.g., Salem, S. & E. Clemente, “A New Experimental Method for EvaluatingDrugs in the Nasal Cavity”, Archives of Otolaryngology, Vol. 96 (1972),pp. 524-529). Antiglaucoma activity is determined by measuringintraocular pressure. (See, e.g., Potter, D., “Adrenergic Pharmacologyof Aqueous Human Dynamics”, Pharmacological Reviews, Vol. 13 (1981), pp.133-153). Antidiarrheal activity is determined by measuring the abilityof the compounds to inhibit prostaglandin-induced diarrhea. (See, e.g.,Thollander, M., P. Hellstrom & T. Svensson, “Suppression of CastorOil-Induced Diarrhea by Alpha-2 Adrenoceptor Agonists”, AlimentaryPharmacology and Therapeutics, Vol. 5 (1991), pp. 255-262). Efficacy intreating irritable bowel syndrome is determined by measuring the abilityof compounds to reduce the stress-induced increase in fecal output.(See, e.g., Barone, F., J. Deegan, W. Price, P. Fowler, J. Fondacaro &H. Ormsbee III, “Cold-restraint stress increases rat fecal pellet outputand colonic transit”, American Journal of Physiology, Vol. 258 (1990),pp. G329-G337). Antiulcer and reduction of hyperchlorhydria efficacy isdetermined by measuring the reduction in gastric acid secretion producedby these compounds (See, e.g., Tazi-Saad, K, J. Chariot, M. Del Tacca &C. Roze, “Effect of α2-adrenoceptor agonists on gastric pepsin and acidsecretion in the rat”, British Journal of Pharmacology, Vol. 106 (1992),pp. 790-796). Antiasthma activity is determined by measuring the effectof the compound on bronchoconstriction associated with pulmonarychallenges such as inhaled antigens. (See, e.g., Chang, J. J. Musser &J. Hand, “Effects of a Novel Leukotriene D₄ Antagonist with5-Lipoxygenase and Cyclooxygenase Inhibitory Activity, Wy-45,911, onLeukotriene-D₄- and Antigen-Induced Bronchoconstriction in Guinea Pig”,International Archives of Allergy and Applied Immunology, Vol. 86(1988), pp. 48-54; and Delehunt, J., A. Perruchound, L. Yerger, B.Marchette, J. Stevenson & W. Abraham, “The Role of Slow-ReactingSubstance of Anaphylaxis in the Late Bronchial Response After AntigenChallenge in Allergic Sheep”, American Reviews of Respiratory Disease,Vol. 130 (1984), pp. 748-754). Activity in cough is determined bymeasuring the number and latency of the cough response to respiratorychallenges such as inhaled citric acid. (See, e.g., Callaway, J. & R.King, “Effects of Inhaled α2-Adrenoceptor and GABA_(B) Receptor Agonistson Citric Acid-Induced Cough and Tidal Volume Changes in Guinea Pigs”,European Journal of Pharmacology, Vol. 220 (1992), pp. 187-195). Thesympatholytic activity of these compounds is determined by measuring thereduction of plasma catecholamines (See, e.g., R. Urban, B. Szabo & K.Starke “Involvement of peripheral presynaptic inhibition in thereduction of sympathetic tone by moxonidine, rilmenidine and UK 14,304”,European Journal of Pharmacology, Vol. 282 (1995), pp. 29-37) or thereduction in renal sympathetic nerve activity (See, e.g., Feng, Q., S.Carlsson, P. Thoren & T. Hedner, “Effects of clonidine on renalsympathetic nerve activity, natriuresis and diuresis in chroniccongestive heart failure rats”, Journal of Pharmacology and ExperimentalTherapeutics, Vol. 261 (1992), pp. 1129-1135), providing the basis fortheir benefit in heart failure and benign prostatic hypertrophy. Thehypotensive effect of these compounds is measure directly as a reductionin mean blood pressure (See, e.g., Timmermans, P. & P. Van Zwieten,“Central and peripheral α-adrenergic effects of some imidazolidines”,European Journal of Pharmacology, Vol. 45 (1977), pp. 229-236). Clinicalstudies have demonstrated the beneficial effect of alpha-2 agonists inthe prevention of myocardial ischemia during surgery (See, e.g., Talke,P., J. Li, U. Jain, J. Leung, K. Drasner, M. Hollenberg & D. Mangano,“Effects of Perioperative Dexmedetomidine Infusion in PatientsUndergoing Vascular Surgery”, Anesthesiology, Vol. 82 (1995), pp.620-633) and in the prevention of angina (See, e.g., Wright, R. A., P.Decroly, T. Kharkevitch & M. Oliver, “Exercise Tolerance in Angina isImproved by Mivazerol—an α2-Adrenoceptor Agonist”, Cardiovascular Drugsand Therapy, Vol. 7 (1993), pp. 929-934). The efficacy of thesecompounds in cardiac reperfusion injury is demonstrated by measuring thereduction of cardiac necrosis and neutrophil infiltration (See, e.g.,Weyrich, A., X. Ma, & A. Lefer, “The Role of L-Arginine in AmelioratingReperfusion Injury After Myocardial Ischemia in the Cat”, Circulation,Vol. 86 (1992), pp. 279-288). The cardiac antiarrhythmic effect of thesecompounds is demonstrated by measuring the inhibition of ouabain inducedarrhythmias (See, e.g., Thomas, G. & P. Stephen, “Effects of TwoImidazolines (ST-91 and ST-93) on the Cardiac Arrhythmias and LethalityInduced by Ouabain in Guinea-Pig”, Asia-Pacific Journal of Pharmacology,Vol. 8 (1993), pp.109-113; and Samson, R., J. Cai, E. Shibata, J.Martins & H. Lee, “Electrophysiological effects of α2-adrenergicstimulation in canine cardiac Purkinje fibers”, American Journal ofPhysiology, Vol. 268 (1995), pp. H2024-H2035). The vasoconstrictoractivity of these compounds is demonstrated by measuring the contractileproperties on isolated arteries and veins in vitro (See, e.g., Flavahan,N., T. Rimele, J. Cooke & M. Vanhoutte, “Characterization ofPostjunctional Alpha-1 and Alpha-2 Adrenoceptors Activated by Exogenousor Nerve-Released Norepinephrine in the Canine Saphenous Vein”, Journalof Pharmacology and Experimental Therapeutics, Vol. 230 (1984), pp.699-705). The effectiveness of these compounds at reducing intracranialpressure is demonstrated by measurement of this property in a caninemodel of subarachnoid hemorrhage (See, e.g., McCormick, J., P.McCormick, J. Zabramski & R. Spetzler, “Intracranial pressure reductionby a central alpha-2 adrenoreceptor agonist after subarachnoidhemorrhage”, Neurosurgery, Vol. 32 (1993), pp. 974-979). The inhibitionof menopausal flushing is demonstrated by measuring the reduction offacial blood flow in the rat (See, e.g., Escoft, K., D. Beattie, H.Connor & S. Brain, “The modulation of the increase in rat facial skinblood flow observed after trigeminal ganglion stimulation”, EuropeanJournal of Pharmacology, Vol. 284 (1995), pp. 69-76) as demonstrated foralpha-2 adrenergic agonists on cutaneous blood flow in the tail (See,e.g., Redfern, W., M. MacLean, R. Clague & J. McGrath, “The role ofalpha-2 adrenoceptors in the vasculature of the rat tail”, BritishJournal of Pharmacology, Vol. 114 (1995), pp. 1724-1730). Theantinociceptive and pain reducing properties of these compounds isdemonstrated by measuring the increase in pain threshold in the rodentwrithing and hot plate antinociceptive models (See, e.g., Millan, M., K.Bervoets, J. Rivet, R. Widdowson, A. Renouard, S, Le Marouille-Girardon& A. Gobert, “Multiple Alpha-2 Adrenergic Receptor Subtypes. II.Evidence for a Role of Rat Alpha-2A Adrenergic Receptors in the Controlof Nociception, Motor Behavior and Hippocampal Synthesis ofNoradrenaline”, Journal of Pharmacology and Experimental Therapeutics,Vol. 270 (1994), pp. 958-972). The antimigraine effect of thesecompounds is demonstrated by measuring the reduction of dural neurogenicinflammation to trigeminal ganglion stimulation in the rat (See, e.g.,Matsubara, T., M. Moskowitz & Z. Huang, “UK-14,304,R(−)-alpha-methyl-histamine and SMS 201-995 block plasma protein leakagewithin dura mater by prejunctional mechanisms”, European Journal ofPharmacology, Vol. 224 (1992), pp. 145-150). The ability of thesecompounds to suppress opiate withdrawal is demonstrated by measuring thesuppression of enhanced sympathetic nerve activity (See, e.g., Franz,D., D. Hare & K. McCloskey, “Spinal sympathetic neurons: possible sitesof opiate-withdrawal suppression by clonidine”, Science, Vol. 215(1982), pp. 1643-1645). Antiepileptic activity of these compounds isdemonstrated by measuring the inhibition of the kindling response (See,e.g., Shouse, M., M. Bier, J. Langer, O. Alcalde, M. Richkind & R.Szymusiak, “The α2-agonist clonidine suppresses seizures, whereas thealpha-2 antagonist idazoxan promotes seizures—a microinfusion study inamygdala-kindled kittens”, Brain Research, Vol. 648 (1994), pp.352-356). The effectiveness of other alpha-2 agonists in the managementof neurologic disorders has been demonstrated, includingattention-deficit hyperactive disorder and Tourette's syndrome (See,eg., Chappell P., M. Riddle, L. Scahill, K. Lynch, R. Schultz, A.Arnsten, J. Leckman & D. Cohen, “Guanfacine treatment of comorbidattention-deficit hyperactivity disorder and Tourette's syndrome:preliminary clinical experience”, Journal of American Academy of Childand Adolescent Psychiatry, Vol. 34 (1995), pp. 1140-1146), cognitivedisorders (See, e.g., Coull, J., “Pharmacological manipulations of theα2-noradrenergic system. Effects on cognition”, Drugs and Aging, Vol. 5(1994), pp. 116-126), and spasticity (See, e.g., Eyssette, M., F.Rohmer, G. Serratrice, J. Warter & D. Boisson, “Multicenter,double-blind trial of a novel antispastic agent, tizanidine, inspasticity associated with multiple sclerosis”, Current Medical Research& Opinion, Vol. 10 (1988), pp. 699-708).

Another aspect of this invention involves methods for preventing ortreating nasal congestion by administering a safe and effective amountof a subject compound to a mammal experiencing or at risk ofexperiencing nasal congestion. Such nasal congestion may be associatedwith human diseases or disorders which include, but are not limited to,seasonal allergic rhinitis, acute upper respiratory viral infections,sinusitis, perennial rhinitis, and vasomotor rhinitis. In addition,other disorders can be generally associated with mucous membranecongestion (for example, otitis media and sinusitis.) Eachadministration of a dose of the subject compound preferably administersa dose within the range of from about 0.0001 mg/kg to about 5 mg/kg of acompound, more preferably from about 0.001 mg/kg to about 0.5 mg/kg.Peroral administration of such doses is preferred. The frequency ofadministration of a subject compound according to this invention ispreferably from about once to about six times daily, more preferablyfrom about once to about 4 times daily. Such doses and frequencies arealso preferred for treating other respiratory conditions, such as,cough, chronic obstructive pulmonary disease (COPD) and asthma. Suchdoses and frequencies are also preferred for treating conditions thatare associated with mucous membrane congestion (for example, sinusitisand otitis media).

Another aspect of this invention involves methods for preventing ortreating glaucoma by administering a safe and effective amount of asubject compound to a mammal experiencing or at risk of experiencingglaucoma. If administered systemically, each administration of a dose ofthe subject compound preferably administers a dose within the range offrom about 0.0001 mg/kg to about 5 mg/kg of a compound, more preferablyfrom about 0.001 mg/kg to about 0.5 mg/kg. If intraocular dosing is usedthen preferably one administers a typical volume (for example, 1 or 2drops) of a liquid composition, comprising from about 0.0001% to about5% of a subject compound, more preferably from about 0.01% to about 0.5%of the compound. Determination of the exact dosage and regimen is withinthe purview of the skilled artisan. Intraocular administration of suchdoses is preferred. The frequency of administration of a subjectcompound according to this invention is preferably from about once toabout six times daily, more preferably from about once to about 4 timesdaily.

Another aspect of this invention involves methods for preventing ortreating gastrointestinal disorders, such as diarrhea, irritable bowelsyndrome, and peptic ulcer by administering a safe and effective amountof a subject compound to a mammal experiencing or at risk ofexperiencing gastrointestinal disorders. Each administration of a doseof the subject compound preferably administers a dose within the rangeof from about 0.0001 mg/kg to about 5 mg/kg of a compound, morepreferably from about 0.001 mg/kg to about 0.5 mg/kg. Peroraladministration of such doses is preferred. The frequency ofadministration of a subject compound according to this invention ispreferably from about once to about six times daily, more preferablyfrom about once to about 4 times daily.

Another aspect of this invention involves methods for preventing ortreating migraine, by administering a safe and effective amount of asubject compound to a mammal experiencing or at risk of experiencingmigraine. Each administration of a dose of the subject compoundpreferably administers a dose within the range of from about 0.0001mg/kg to about 5 mg/kg of a compound, more preferably from about 0.001mg/kg to about 0.5 mg/kg. Peroral, parenteral or intranasaladministration of such doses is preferred. The frequency of peroraladministration of a subject compound according to this invention ispreferably from about once to about six times daily, more preferablyfrom about once to about 4 times daily. The frequency of parenteraldosing of a subject compound according to this invention is preferablyfrom about once to about six times daily, more preferably from aboutonce to about 4 times daily or by infusion to the desired effect. Thefrequency of intranasal dosing of a subject compound according to thisinvention is preferably from about once to about six times daily, morepreferably from about once to about 4 times daily.

Another aspect of this invention involves methods for preventing ortreating disorders related to sympathetic nervous system activity, suchas hypertension, myocardial ischemia, cardiac reperfusion injury,angina, cardiac arrhythmia, and benign prostatic hypertrophy, byadministering a safe and effective amount of a subject compound to amammal experiencing or at risk of experiencing these diseases ordisorders. Each administration of a dose of the subject compoundpreferably administers a dose within the range of from about 0.0001mg/kg to about 5 mg/kg of a compound, more preferably from about 0.001mg/kg to about 0.5 mg/kg. Peroral and parenteral administration of suchdoses are preferred. The frequency of peroral administration of asubject compound according to this invention is preferably from aboutonce to about six times daily, more preferably from about once to about4 times daily. The frequency of parenteral dosing of a subject compoundaccording to this invention is preferably from about once to about sixtimes daily, more preferably from about once to about 4 times daily orby infusion to the desired effect.

Another aspect of this invention involves methods for preventing ortreating pain, by administering a safe and effective amount of a subjectcompound to a mammal experiencing or at risk of experiencing pain. Eachadministration of a dose of the subject compound preferably administersa dose within the range of from about 0.0001 mg/kg to about 5 mg/kg of acompound, more preferably from about 0.001 mg/kg to about 0.5 mg/kg.Peroral or parenteral administration of such doses is preferred. Thefrequency of peroral administration of a subject compound according tothis invention is preferably from about once to about six times daily,more preferably from about once to about 4 times daily. The frequency ofparenteral dosing of a subject compound according to this invention ispreferably from about once to about six times daily, more preferablyfrom about once to about 4 times daily or by infusion to the desiredeffect.

Another aspect of this invention involves methods for preventing ortreating substance abuse and the abstinence syndrome resulting fromwithdrawal of these substances, such as alcohol and opiates, byadministering a safe and effective amount of a subject compound to amammal experiencing or at risk of experiencing substance abuse orwithdrawal symptoms. Each administration of a dose of the subjectcompound preferably administers a dose within the range of from about0.0001 mg/kg to about 5 mg/kg of a compound, more preferably from about0.001 mg/kg to about 0.5 mg/kg. Peroral administration of such doses ispreferred. The frequency of administration of a subject compoundaccording to this invention is preferably from about once to about sixtimes daily, more preferably from about once to about 4 times daily.

Composition and Method Examples

The following non-limiting examples illustrate the compositions andmethods of use of this invention.

Example A Oral Tablet Composition Ingredient Amount per tablet (mg)Subject Compound 4 20.0 Microcrystalline cellulose 80.0 (Avicel PH102 ®) Dicalcium phosphate 96.0 Pyrogenic silica (Cab-O-Sil ®) 1.0Magnesium stearate 3.0 Total = 200.0 mg

One tablet is swallowed by a patient with nasal congestion. Thecongestion is substantially diminished.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example B Chewable Tablet Composition Ingredient Amount per tablet (mg)Subject Compound 1 15.0 Mannitol 255.6 Microcrystalline cellulose 100.8(Avicel PH 101 ®) Dextrinized sucrose (Di-Pac ®) 199.5 Imitation orangeflavor 4.2 Sodium saccharin 1.2 Stearic acid 15.0 Magnesium stearate 3.0FD&C Yellow #6 dye 3.0 Pyrogenic silica (Cab-O-Sil ®) 2.7 Total = 600.0mg

One tablet is chewed and swallowed by a patient with nasal congestion.The congestion is substantially reduced.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example C Sublingual Tablet Composition Ingredient Amount per tablet(mg) Subject Compound 5 2.00 Mannitol 2.00 Microcrystalline cellulose29.00 (Avicel PH 101 ®) Mint flavorants 0.25 Sodium saccharin 0.08 Total= 33.33 mg

One tablet is placed under the tongue of a patient with nasal congestionand allowed to dissolve. The congestion is rapidly and substantiallydiminished.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example D Intranasal Solution Composition Ingredient Composition (% w/v)Subject Compound 3 0.20 Benzalkonium chloride 0.02 Thimerosal 0.002d-Sorbitol 5.00 Glycine 0.35 Aromatics 0.075 Purified water q.s. Total =100.00

One-tenth of a mL of the composition is sprayed from a pump actuatorinto each nostril of a patient with nasal congestion. The congestion issubstantially diminished.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example E Intranasal Gel Composition Ingredient Composition (% w/v)Subject Compound 1 0.10 Benzalkonium chloride 0.02 Thimerosal 0.002Hydroxypropyl methylcellulose 1.00 (Metolose 65SH4000 ®) Aromatics 0.06Sodium chloride (0.65%) q.s. Total = 100.00

One-fifth of a mL of the composition is applied as drops from a dropperinto each nostril of a patient with nasal congestion. The congestion issubstantially reduced.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example F Inhalation Aerosol Composition Ingredient Composition (% w/v)Subject Compound 2 5.0 Alcohol 33.0 Ascorbic acid 0.1 Menthol 0.1 SodiumSaccharin 0.2 Propellant (F12, F114) q.s. Total = 100.0

Two-puffs of the aerosol composition is inhaled from a metered-doseinhaler by a patient with asthma. The asthmatic condition is effectivelyrelieved.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example G Topical Ophthalmic Composition Ingredient Composition (% w/v)Subject Compound 5 0.10 Benzalkonium chloride 0.01 EDTA 0.05Hydroxyethylcellulose (Natrosol M ®) 0.50 Sodium metabisulfite 0.10Sodium chloride (0.9%) q.s. Total = 100.0

One-tenth of a mL of the composition is administered directly into eacheye of a patient with glaucoma. The intraocular pressure issubstantially reduced.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example H Oral Liquid Composition Ingredient Amount/15 mL Dose SubjectCompound 4 15 mg Chlorpheniramine maleate 4 mg Propylene glycol 1.8 gEthanol (95%) 1.5 mL Methanol 12.5 mg Eucalyptus oil 7.55 mg Flavorants0.05 mL Sucrose 7.65 g Carboxymethylcellulose (CMC) 7.5 mgMicrocrystalline cellulose and 187.5 mg Sodium CMC (Avicel RC 591 ®)Polysorbate 80 3.0 mg Glycerin 300 mg Sorbitol 300 mg FD&C Red #40 dye 3mg Sodium saccharin 22.5 mg Sodium phosphate monobasic 44 mg Sodiumcitrate monohydrate 28 mg Purified Water q.s. Total = 15 mL

One 15 mL dose of the liquid composition is swallowed by a patient withnasal congestion and runny nose due to allergic rhinitis. The congestionand runny nose are effectively reduced.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example J Oral Liquid Composition Ingredient Amount/15 mL Dose SubjectCompound 2 30 mg Sucrose 8.16 g Glycerin 300 mg Sorbitol 300 mgMethylparaben 19.5 mg Propylparaben 4.5 mg Menthol 22.5 mg Eucalyptusoil 7.5 mg Flavorants 0.07 mL FD&C Red #40 dye 3.0 mg Sodium saccharin30 mg Purified water q.s. Total = 15 mL

One 15 mL dose of the alcohol-free liquid medication is swallowed by apatient with nasal congestion. The congestion is substantiallydiminished.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example K Oral Tablet Composition Ingredient Amount per tablet (mg)Subject Compound 1 4 Microcrystalline cellulose, NF 130 Starch 1500, NF100 Magnesium stearate, USP 2 Total = 236 mg

One tablet is swallowed by a patient with migraine. The pain and aura ofmigraine is substantially diminished.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example L Oral Tablet Composition Ingredient Amount per tablet (mg)Subject Compound 2 12 Hydroxypropyl methylcellulose, USP 12 Magnesiumstearate, USP 2 Lactose anhydrous, USP 200 Total = 226 mg

For the relief of pain. Adults 12 and over take one tablet every twelvehours.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example M Oral Caplet Composition Ingredient Amount per tablet (mg)Naproxen sodium anhydrous, USP 220 Subject Compound 3 6 Hydroxypropylmethylcellulose, USP 6 Magnesium stearate, USP 2 Povidone K-30, USP 10Talc, USP 12 Microcrystalline cellulose, NF 44 Total = 300 mg

For relief of symptoms associated with the common cold, sinusitis, orflu including nasal congestion, headache, fever, body aches, and pains.Adults 12 and over take two caplets every twelve hours.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example N Oral Tablet Composition Ingredient Amount per tablet (mg)Subject Compound 4 6 Hydroxypropyl methylcellulose, USP 6 Silicondioxide, colloidal, NF 30 Pregelatinized starch, NF 50 Magnesiumstearate, USP 4 Total = 96 mg

For treatment of benign prostatic hypertrophy. Take one tablet per day.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example O Oral Tablet Composition Ingredient Amount per caplet (mg)Subject Compound 5 6 Hydroxypropyl methylcellulose, USP 6 Magnesiumstearate, USP 2 Povidone K-30, USP 10 Talc, USP 12 Microcrystallinecellulose, NF 44 Total = 80 mg

For the use in the treatment of alcoholism or opiate addiction. Adults12 and over take two caplets every twelve hours.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example P Oral Tablet Composition Ingredient Amount per tablet (mg)Subject Compound 1 6 Hydroxypropyl methylcellulose, USP 12 Magnesiumstearate, USP 2 Povidone K-30, USP 10 Talc, USP 12 Microcrystallinecellulose, NF 44 Total = 86 mg

For the treatment of ulcer and hyperacidity. Take two tablets asappropriate.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example Q Oral Tablet Composition Ingredient Amount per tablet (mg)Component Amount Subject Compound 5 10 mg/ml carrier Carrier: Sodiumcitrate buffer with (percent by weight of carrier): Lecithin 0.48%Carboxymethylcellulose 0.53 Povidone 0.50 Methyl paraben 0.11 Propylparaben 0.011

For the reduction of cardiac reperfusion injury.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example R Oral Liquid Composition Ingredient Amount/fl oz Dose (mg)Acetaminophen, USP 1000 Doxylamine succinate, USP 12.5 Dextromethorphanhydrobromide, USP 30 Subject Compound 2 6 Dow XYS-40010.00 resin 3 Highfructose corn syrup 16000 Polyethylene glycol, NF 3000 Propylene glycol,USP 3000 Alcohol, USP 2500 Sodium citrate dihydrate, USP 150 Citricacid, anhydrous, USP 50 Saccharin sodium, USP 20 Flavor 3.5 Purifiedwater, USP 3500 Total = 29275 mg/fl oz

For the relief of minor aches, pains, headache, muscular aches, sorethroat pain, and fever associated with a cold or flu. Relieves nasalcongestion, cough due to minor throat and bronchial irritations, runnynose, and sneezing associated with the common cold. Adults 12 and overtake one fluid ounce every six hours.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example S Oral Liquid Composition Ingredient Amount/fl oz Dose (mg)Naproxen sodium anhydrous, USP 220 Doxylamine succinate, USP 12.5Dextromethorphan hydrobromide, USP 30 Subject Compound 1 6 DowXYS-40010.00 resin 3 High fructose corn syrup 16000 Polyethylene glycol,NF 3000 Propylene glycol, USP 3000 Alcohol, USP 2500 Sodium citratedihydrate, USP 150 Citric acid, anhydrous, USP 50 Saccharin sodium, USP20 Flavor 3.5 Purified water, USP 3800 Total = 28795 mg/fl oz

For the relief of minor aches, pains, headache, muscular aches, sorethroat pain, and fever associated with a cold or flu. Relieves nasalcongestion, cough due to minor throat and bronchial irritations, runnynose, and sneezing associated with the common cold. Adults 12 and overtake one fluid ounce every six hours.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

COMPOSITION EXAMPLE T

A composition for parenteral administration, according to thisinvention, is made comprising:

Component Amount Subject Compound I 10 mg/ml carrier Carrier: Sodiumcitrate buffer with (percent by weight of carrier): Lecithin 0.48%Carboxymethylcellulose 0.53 Povidone 0.50 Methyl paraben 0.11 Propylparaben 0.011

The above ingredients are mixed, forming a solution. Approximately 2.0ml of the solution is administered, intravenously, to a human subjectsuffering from septic or cardiogenic shock. The symptoms subside.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example U Oral Tablet Composition Ingredient Amount per tablet (mg)Subject Compound 5 10 Hydroxypropyl methylcellulose, USP 12 Magnesiumstearate, USP 2 Povidone K-30, USP 10 Talc, USP 12 Microcrystallinecellulose, NF 44 Total = 90 mg

For the treatment of cardiac arrhythmia. Take as prescribed.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Example V Oral Tablet Composition Ingredient Amount per tablet (mg)Subject Compound 1 4 Microcrystalline cellulose, NF 130 Starch 1500, NF100 Magnesium stearate, USP 2 Total = 236 mg

For the treatment of congestive heart failure. Take as prescribed.

Other compounds having a structure according to Formula I are used withsubstantially similar results.

Modification of the preceding embodiments is within the scope of theskilled artisan in formulation, given the guidance of the specificationin light of the state of the art.

Other examples of combination actives are contemplated. Examples ofmedicaments which can be combined with the primary active are includedin U.S. Pat. No. 4,552,899 to Sunshine, et al., hereby incorporated byreference. All other references referred to throughout thisspecification are hereby incorporated by reference.

While particular embodiments of this invention have been described, itwill be obvious to those skilled in the art that various changes andmodifications of this invention can be made without departing from thespirit and scope of the invention. It is intended to cover, in theappended claims, all such modifications that are within the scope ofthis invention.

What is claimed is:
 1. A compound of formula;

wherein; a) R₁ is hydrogen; or alkyl or nil; where R₁ is nil, bond (α)is a double bond; b) D is CR₂ and R₂ is selected from hydrogen;unsubstituted C₁-C₃ alkanyl; amino, hydroxy, mercapto; C₁-C₃ alkylthioor alkoxy; C₁-C₃ alkylamino or C₁-C₃ dialkylamino and halo; or when B isCR₃; D may be N; c) B is NR₉, CR₃, S, O, SO or SO₂; wherein R₉ isselected from hydrogen; and unsubstituted C₁-C₃ alkanyl, alkenyl oralkynyl; cycloalkanyl, cycloalkenyl; and wherein R₃ and R₈ are eachindependently selected from hydrogen; unsubstituted C₁-C₃ alkanyl,alkenyl or alkynyl; cycloalkanyl, cycloalkenyl; unsubstituted C₁-C₃alkylthio or alkoxy; hydroxy; thio; nitro; cyano; amino; C₁-C₃alkylamino or C₁-C₃ dialkylamino and halo; d) R₄, R₅ and R₆ are eachindependently selected from hydrogen; unsubstituted C₁-C₃ alkanyl,alkenyl or alkynyl; cycloalkanyl, cycloalkenyl; unsubstituted C₁-C₃alkylthio or alkoxy; hydroxy; thio; nitro; cyano; amino; C₁-C₃alkylamino or C₁-C₃ dialkylamino; halo; and NH—C(═NR₁₀)NHR₁₁(guanidinyl); wherein R₁₀ and R₁₁ are independently selected fromhydrogen; methyl; and ethyl; and wherein one and only one of R₄, R₅ andR₆ is guanidinyl; e) R₇ is selected from hydrogen; unsubstituted C₁-C₃alkanyl, alkenyl or alkynyl; cycloalkanyl, cycloalkenyl; unsubstitutedC₁-C₃ alkylthio or alkoxy; hydroxy; thio; nitro; cyano; amino; C₁-C₃alkylamino or C₁-C₃ dialkylamino and halo; or its enantiomer, opticalisomer, stereoisomer, diastereomer, tautomer, addition salt, orbiohydrolyzable amide or ester.
 2. A compound according to claim 1wherein R₆ is guanidinyl and R₁₁ is hydrogen.
 3. A compound according toclaim 2 wherein B is NR₉ and D is CR₂.
 4. A compound according to claim3 wherein: R₂, R₉ and R₁₀ are each independently chosen from hydrogenand methyl; R₄ is selected from hydrogen, methyl, methoxy, fluoro,chloro, bromo and cyano; R₅ is hydrogen; and R₇ is selected from methyl,chloro, and bromo.
 5. A compound according to claim 2 wherein B is S andD is CR₂, and R₁ is nil.
 6. A compound according to claim 5 wherein R₂and R₁₀ are each independently selected from hydrogen and methyl; R₄ isselected from hydrogen, methyl, methoxy, fluoro, chloro, bromo andcyano; R₅ is hydrogen; and R₇ is selected from methyl, chloro, andbromo.
 7. A compound according to claim 5 wherein R₂ and R₁₀ are eachindependently selected from hydrogen and methyl; R₄ is selected fromhydrogen, methyl, methoxy, fluoro, chloro, bromo and cyano; R₅ ismethyl, chloro or bromo; and R₇ is hydrogen.
 8. The compound accordingto claim 2, wherein: R₄ is selected from hydrogen; unsubstituted C₁-C₃alkanyl, alkenyl or alkynyl; unsubstituted C₁-C₃ alkylthio or alkoxy;hydroxy; thio; nitro; cyano; amino; and C₁-C₂ alkylamino or C₁-C₂dialkylamino and halo; R₅ is hydrogen; and R₇ is selected from hydrogen;unsubstituted C₁-C₃ alkanyl, alkenyl or alkynyl; unsubstituted C₁-C₃alkylthio or alkoxy; and C₁-C₂ alkylamino or C₁-C₂ dialkylamino; andhalo.
 9. The compound according to claim 1, wherein R₅ is guanidinyl andR₁₁ is hydrogen.
 10. A compound according to claim 9 wherein B is S andD is CR₂ and R₁ is nil.
 11. A compound according to claim 10 wherein R₂and R₁₀ are each independently selected from hydrogen and methyl; R₄ isselected from methyl, chloro, and bromo; R₆ is hydrogen; and R₇ isselected from methyl, methoxy, chloro, bromo, and cyano.
 12. Thecompound according to claim 1, wherein R₄ is guanidinyl.
 13. Thecompound of claim 12 wherein B is chosen from NR₉ and S.
 14. Thecompound according to claim 13, wherein: R₅, R₆ and R₇ are eachindependently selected from hydrogen; methyl; ethyl; methoxy;methylthio; thio; cyano; amino; and halo; and R₂ is hydrogen.
 15. Thecompound according to claim 1, wherein the compound is:(4,7-Dimethylbenzimidazol-5-yl)guanidine;(2,4-Dimethylbenzimidazol-5-yl)guanidine;(1,4-Dimethylbenzimidazol-5-yl)guanidine;(4-Bromobenzimidazol-5-yl)guanidine;N¹-Methyl-N²-(4-methylbenzimidazol-5-yl)guanidine;(6-Methylbenzothiazol-5-yl)guanidine; or(4-Bromobenzothiazol-5-yl)guanidine.
 16. The compound according to claim1, wherein the compound is: (4-Methylbenzimidazol-5-yl)guanidine.
 17. Apharmaceutical composition comprising: (a) a safe and effective amountof a compound of claim 1; and (b) a pharmaceutically-acceptable carrier.18. A pharmaceutical composition comprising the compound of claim 1 andone or more actives chosen from the group consisting of anantihistamine, antitussive, mast cell stabilizer, leukotrieneantagonist, expectorant/mucolytic, antioxidant or radical inhibitor,steroid, bronchodilator, antiviral, analgesic, antiinflammatory,gastrointestinal and ocular active.
 19. A pharmaceutical compositionaccording to claim 17 further comprising an antihistamine.
 20. Apharmaceutical composition according to claim 17 further comprising anantiinflammatory.
 21. A method for preventing or treating a disordermodulated by alpha-2 adrenoceptors, by administering to a mammal in needof such treatment, a safe and effective amount of an alpha-2adrenoceptor agonist compound according to claim
 1. 22. A method forpreventing or treating a disorder modulated by alpha-2 adrenoceptors,wherein the disorder is chosen from the groups comprising, nasalcongestion, otitis media, sinusitis, asthma, pain, migraine, substanceabuse and addiction, gastrointestinal disorder, ulcer, stomachhyperacidity, benign prostatic hypertrophy, by administering to a mammalin need of such treatment, a safe and effective amount of an alpha-2adrenoceptor agonist compound according to claim
 1. 23. A method oftreating or preventing nasal congestion by administering to a mammal inneed of such treatment a safe and effective amount of a compoundaccording to claim
 1. 24. A method of treating or preventing nasalcongestion by administering to a mammal in need of such treatment a safeand effective amount of a compound according to claim
 16. 25. The methodof claim 22, wherein the disorder is otitis media.
 26. The method ofclaim 22, wherein the disorder is sinusitis.
 27. A method for preventingor treating a respiratory disorder, wherein the disorder is chosen fromthe group comprising cough, chronic obstructive pulmonary disease andasthma, by administering to a mammal in need of such treatment, a safeand effective amount of a compound according to claim
 1. 28. A methodfor preventing or treating a respiratory disorder according to claim 27,wherein the disorder is asthma.
 29. A method for preventing or treatingdisorders mediated by sympathetic activity and modulated by alpha-2adrenoceptors by administering to a mammal in need of such treatment, asafe and effective amount of an alpha-2 adrenoceptor agonist compoundaccording to claim
 1. 30. A method of treating a disorder according toclaim 29, wherein the disorder is chosen from the group comprisingbenign prostatic hypertrophy, myocardial ischemia, cardiac reperfusioninjury, angina, cardiac arrhythmia, heart failure and hypertension. 31.The method of claim 30, wherein the disorder is heart failure.
 32. Amethod for preventing or treating an ocular disorder modulated byalpha-2 adrenoceptors, by administering to a mammal in need of suchtreatment, a safe and effective amount of a compound according to claim1.
 33. A method for preventing or treating an ocular disorder accordingto claim 32 wherein the disorder is chosen from the group comprisingocular hypertension, glaucoma, hyperemia, conjunctivitis, and uveitisand glaucoma.
 34. A method for preventing or treating an ocularhypertensive disorder according to claim 33 wherein the disorder isglaucoma.
 35. A method for preventing or treating a gastrointestinaldisorder modulated by alpha-2 adrenoceptors by administering to a mammalin need of such treatment, a safe and effective amount of an alpha-2adrenoceptor agonist compound according to claim
 1. 36. A method forpreventing or treating a gastrointestinal disorder, according to claim35, wherein the disorder is chosen from the group comprising diarrheaand irritable bowel syndrome.
 37. A method for preventing or treating agastrointestinal disorder, according to claim 36, wherein the disorderis diarrhea.
 38. A method for preventing or treating migraine byadministering to a mammal in need of such treatment, a safe andeffective amount of a compound according to claim
 1. 39. A method forpreventing or treating pain by administering to a mammal in need of suchtreatment, a safe and effective amount of a compound according to claim1.
 40. A method for treating substance abuse by administering to amammal in need of such treatment, a safe and effective amount of acompound according to claim 1.